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Abstract:

Provided herein are methods of treating, preventing and/or managing
cancers, which comprise administering to a patient
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or an
enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof.

Claims:

1. A method of treating or managing cancer, comprising administering to a
patient in need of such treatment or management a therapeutically
effective amount of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, which
has the following structure: ##STR00004## or an enantiomer or mixture
of enantiomers thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof.

8. The method of claim 1, wherein the cancer is non-Hodgkin's lymphoma.

9. The method of claim 8, wherein the non-Hodgkin's lymphoma is diffuse
large B-cell lymphoma.

10. The method of claim 9, wherein the diffuse large B-cell lymphoma is
of the activated B-cell phenotype.

11. The method of claim 10, wherein the diffuse large B-cell lymphoma is
characterized by the expression of one or more biomarkers overexpressed
in RIVA, U2932, TMD8 or OCI-Ly10 cell lines.

12. The method of claim 1, wherein the cancer is relapsed or refractory.

13. The method of claim 1, wherein the cancer is drug-resistant.

14. A method for treating or managing non-Hodgkin's lymphoma, comprising:
(i) identifying a patient having non-Hodgkin's lymphoma sensitive to
treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione; and
(ii) administering to the patient a therapeutically effective amount of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione or a
pharmaceutically acceptable salt, solvate or hydrate thereof.

15. The method of claim 14, wherein the non-Hodgkin's lymphoma is diffuse
large B-cell lymphoma.

16. The method of claim 14, wherein the non-Hodgkin's lymphoma is of the
activated B-cell phenotype.

17. The method of claim 15, wherein the diffuse large B-cell lymphoma is
of the activated B-cell phenotype.

18. The method of claim 17, wherein the diffuse large B-cell lymphoma is
characterized by the expression of one or more biomarkers overexpressed
in RIVA, U2932, TMD8 or OCI-Ly10 cell lines.

19. The method of claim 14, wherein identifying a patient having
non-Hodgkin's lymphoma sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or a
salt, solvate or hydrate thereof, comprises characterization of the
non-Hodgkin's lymphoma phenotype of the patient as an activated B-cell
subtype.

20. The method of claim 19, wherein the non-Hodgkin's lymphoma phenotype
is characterized as an activated B-cell subtype of diffuse large B-cell
lymphoma.

21. The method of claim 19, wherein the non-Hodgkin's lymphoma phenotype
is characterized by the expression of one or more biomarkers
overexpressed in RIVA, U2932, TMD8 or OCI-Ly10 cell lines.

22. The method of claim 14, wherein identification of the non-Hodgkin's
lymphoma phenotype comprises obtaining a biological sample from a patient
having lymphoma.

23. The method of claim 22, wherein the biological sample is a lymph node
biopsy, a bone marrow biopsy, or a sample of peripheral blood tumor
cells.

24. The method of claim 14, wherein identifying a patient having
non-Hodgkin's lymphoma sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or a
salt, solvate or hydrate thereof, comprises identification of a gene
associated with the activated B-cell phenotype.

25. The method of claim 24, wherein the gene associated with the
activated B-cell phenotype is selected from the group consisting of
IRF4/MUM1, FOXP1, SPIB, CARD11 and BLIMP/PDRM1.

26. The method of claim 14, wherein identifying a patient having
non-Hodgkin's lymphoma sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or a
salt, solvate or hydrate thereof, comprises measuring the level of
NF-.kappa.B activity in a biological sample obtained from the patient.

27. The method of claim 26, wherein the biological sample is a lymph node
biopsy, a bone marrow biopsy, or a sample of peripheral blood tumor
cells.

29. The method of claim 1, wherein the compound is
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrochloride, or a salt, solvate or hydrate thereof.

30. The method of claim 1, further comprising the administration of a
therapeutically effective amount of one or more additional active agents.

31. The method of claim 30, wherein the additional active agent is
selected from the group consisting of an alkylating agent, an adenosine
analog, a glucocorticoid, a kinase inhibitor, a SYK inhibitor, a PDE3
inhibitor, a PDE7 inhibitor, doxorubicin, chlorambucil, vincristine,
bendamustine, forskolin and rituximab.

32. The method of claim 31, wherein the additional active agent is
rituximab.

33. The method of claim 1, wherein
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or a
pharmaceutically acceptable salt, solvate or hydrate thereof is
administered in an amount of from about 0.5 to about 50 mg per day.

34. The method of claim 33, wherein the compound is administered in an
amount of about 0.5 to about 5 mg per day.

35. The method of claim 33, wherein the compound is administered in an
amount of about 0.5, 1, 2, 4, 5, 10, 15, 20, 25 or 50 mg per day.

36. The method of claim 33, wherein the compound is orally administered.

37. The method of claim 33, wherein the compound is administered in a
capsule or tablet.

38. The method of claim 37, wherein the compound is administered in 10 mg
or 25 mg of a capsule.

39. The method of claim 1, wherein the diffuse large B-cell lymphoma is
relapsed, refractory or resistant to conventional therapy.

40. The method of claim 1, wherein the compound is administered for 21
days followed by seven days rest in a 28 day cycle.

41. A method for predicting tumor response to treatment in a
non-Hodgkin's lymphoma patient, comprising: (i) obtaining a biological
sample from the patient; (ii) measuring the level of NF-.kappa.B activity
in the biological sample; and (iii) comparing the level of NF-.kappa.B
activity in the biological sample to that of a biological sample of a
non-activated B-cell lymphoma subtype; wherein an increased level of
NF-.kappa.B activity relative to non-activated B-cell subtype lymphoma
cells indicates a likelihood of an effective patient tumor response to
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
treatment.

42. A method of monitoring tumor response to treatment in a non-Hodgkin's
lymphoma patient, comprising: (i) obtaining a biological sample from the
patient; (ii) measuring the level of NF-.kappa.B activity in the
biological sample; (iii) administering a therapeutically effective amount
of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or
a salt, solvate or hydrate thereof to the patient; (iv) obtaining a
second biological sample from the patient; (v) measuring the level of
NF-.kappa.B activity in the second biological sample; and (vi) comparing
the level of NF-.kappa.B activity in the first biological sample to that
in the second biological sample; wherein a decreased level of NF-.kappa.B
activity in the second biological sample relative to the first biological
sample indicates a likelihood of an effective patient tumor response.

43. A method for monitoring patient compliance with a drug treatment
protocol in a non-Hodgkin's lymphoma patient, comprising: (i) obtaining a
biological sample from the patient; (ii) measuring the level of
NF-.kappa.B activity in the biological sample; and (iii) comparing the
level of NF-.kappa.B activity in the biological sample to a control
untreated sample; wherein a decreased level of NF-.kappa.B activity in
the biological sample relative to the control indicates patient
compliance with the drug treatment protocol.

44. The method of claim 1, wherein the non-Hodgkin's lymphoma is diffuse
large B-cell lymphoma.

45. The method of claim 1, wherein the level of NF-.kappa.B activity is
measured by an enzyme-linked immunosorbent assay.

46. A method for predicting tumor response to treatment in a
non-Hodgkin's lymphoma patient, comprising: (i) obtaining a biological
sample from the patient; (ii) purifying protein or RNA from the sample;
and (iii) identifying increased expression of a gene associated with the
activated B-cell phenotype of non-Hodgkin's lymphoma relative to control
non-activated B-cell phenotype of non-Hodgkin's lymphoma; wherein
increased expression of a gene associated with the activated B-cell
phenotype of non-Hodgkin's lymphoma indicates a likelihood of an
effective patient tumor response to
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
treatment.

47. The method of claim 46, wherein the biological sample is tumor
tissue.

48. The method of claim 46, wherein increased expression is an increase
of about 1.5.times., 2.0.times., 3.times., 5.times., or more.

49. The method of claim 1, wherein the gene associated with the activated
B-cell phenotype is selected from the group consisting of IRF4/MUM1,
FOXP1, SPIB, CARD11 and BLIMP/PDRM1.

50. The method of claim 41, wherein identifying the expression of a gene
associated with the activated B-cell phenotype of non-Hodgkin's lymphoma
is performed by quantitative real-time PCR.

51. A kit for predicting tumor response to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or a
salt, solvate or hydrate thereof, in a non-Hodgkin's lymphoma patient,
comprising: (i) a solid support; and (ii) a means for detecting the
expression of a biomarker of an activated B-cell phenotype of
non-Hodgkin's lymphoma in a biological sample.

52. The kit of claim 51, wherein the biomarker is NF-.kappa.B.

53. The kit of claim 51, wherein the biomarker is a gene associated with
the activated B-cell phenotype and is selected from the group consisting
of IRF4/MUM1, FOXP1, SPIB, CARD11 and BLIMP/PDRM1.

54. A method of selecting a group of cancer patients based on the level
of CRBN expression, or the levels of DDB1, DDB2, IRF4 or NFκB
expression within the cancer, for the purposes of predicting clinical
response, monitoring clinical response, or monitoring patient compliance
to dosing by
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, a
stereoisomer thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof; wherein the cancer
patients are selected from multiple myeloma, non-Hodgkin's lymphoma,
diffuse large B-cell lymphoma, melanoma and solid tumor patients.

57. The method of claim 54, wherein the method of selecting a group of
cancer patients is based on the level of DDB1 expression within the
cancer.

58. The method of claim 54, wherein the method of selecting a group of
cancer patients is based on the level of DDB2 expression within the
cancer.

59. The method of claim 54, wherein the method of selecting a group of
cancer patients is based on the level of IRF4 expression within the
cancer.

60. The method of claim 54, wherein the method of selecting a group of
cancer patients is based on the level of NFκB expression within the
cancer.

61. A method of selecting a group of cancer patients responsive to
treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, a
stereoisomer thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof; based on the level
of CRBN expression, or the levels of DDB1, DDB2, IRF4 or NFκB
expression within the patient's T cells, B cells, or plasma cells, for
the purposes of predicting clinical response, monitoring clinical
response, or monitoring patient compliance to dosing by
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, a
stereoisomer thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof.

Description:

[0001] This application claims the benefit of U.S. Provisional Patent
Application No. 61/451,995, filed on Mar. 11, 2011, and U.S. Provisional
Patent Application No. 61/480,272, filed on Apr. 28, 2011, the entireties
of which are incorporated herein by reference.

1. FIELD OF THE INVENTION

[0002] Provided herein are methods of treating, preventing and/or managing
cancers, which comprise administering to a patient
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or an
enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof.

2. BACKGROUND OF THE INVENTION

2.1 Pathobiology of Cancer

[0003] Cancer is characterized primarily by an increase in the number of
abnormal cells derived from a given normal tissue, invasion of adjacent
tissues by these abnormal cells, or lymphatic or blood-borne spread of
malignant cells to regional lymph nodes and to distant sites
(metastasis). Clinical data and molecular biologic studies indicate that
cancer is a multistep process that begins with minor preneoplastic
changes, which may under certain conditions progress to neoplasia. The
neoplastic lesion may evolve clonally and develop an increasing capacity
for invasion, growth, metastasis, and heterogeneity, especially under
conditions in which the neoplastic cells escape the host's immune
surveillance. Roitt, I., Brostoff, J and Kale, D., Immunology, 17.1-17.12
(3rd ed., Mosby, St. Louis, Mo., 1993).

[0004] There is an enormous variety of cancers which are described in
detail in the medical literature. Examples include cancer of the lung,
colon, rectum, prostate, breast, brain, and intestine. The incidence of
cancer continues to climb as the general population ages, as new cancers
develop, and as susceptible populations (e.g., people infected with AIDS
or excessively exposed to sunlight) grow. A tremendous demand therefore
exists for new methods and compositions that can be used to treat
patients with cancer.

[0005] Many types of cancers are associated with new blood vessel
formation, a process known as angiogenesis. Several of the mechanisms
involved in tumor-induced angiogenesis have been elucidated. The most
direct of these mechanisms is the secretion by the tumor cells of
cytokines with angiogenic properties. Examples of these cytokines include
acidic and basic fibroblastic growth factor (a,b-FGF), angiogenin,
vascular endothelial growth factor (VEGF), and TNF-α.
Alternatively, tumor cells can release angiogenic peptides through the
production of proteases and the subsequent breakdown of the extracellular
matrix where some cytokines are stored (e.g., b-FGF). Angiogenesis can
also be induced indirectly through the recruitment of inflammatory cells
(particularly macrophages) and their subsequent release of angiogenic
cytokines (e.g., TNF-α, b-FGF).

[0006] Lymphoma refers to cancers that originate in the lymphatic system.
Lymphoma is characterized by malignant neoplasms of lymphocytes--B
lymphocytes and T lymphocytes (i.e., B-cells and T-cells). Lymphoma
generally starts in lymph nodes or collections of lymphatic tissue in
organs including, but not limited to, the stomach or intestines. Lymphoma
may involve the marrow and the blood in some cases. Lymphoma may spread
from one site to other parts of the body.

[0008] Non-Hodgkin's lymphoma (NHL) is the fifth most common cancer for
both men and women in the United States, with an estimated 63,190 new
cases and 18,660 deaths in 2007. Jemal A, et al., CA Cancer J Clin 2007;
57(1):43-66. The probability of developing NHL increases with age and the
incidence of NHL in the elderly has been steadily increasing in the past
decade, causing concern with the aging trend of the US population. Id.
Clarke C A, et al., Cancer 2002; 94(7):2015-2023.

[0009] Diffuse large B-cell lymphoma (DLBCL) accounts for approximately
one-third of non-Hodgkin's lymphomas. While some DLBCL patients are cured
with traditional chemotherapy, the remainder die from the disease.
Anticancer drugs cause rapid and persistent depletion of lymphocytes,
possibly by direct apoptosis induction in mature T and B cells. See K.
Stahnke et al., Blood 2001, 98:3066-3073. Absolute lymphocyte count (ALC)
has been shown to be a prognostic factor in follicular non-Hodgkin's
lymphoma and recent results have suggested that ALC at diagnosis is an
important prognostic factor in diffuse large B-cell lymphoma. See D. Kim
et al., Journal of Clinical Oncology, 2007 ASCO Annual Meeting
Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 8082.

[0010] Leukemia refers to malignant neoplasms of the blood-forming
tissues. Various forms of leukemias are described, for example, in U.S.
Pat. No. 7,393,862 and U.S. provisional patent application No.
60/380,842, filed May 17, 2002, the entireties of which are incorporated
herein by reference. Although viruses reportedly cause several forms of
leukemia in animals, causes of leukemia in humans are to a large extent
unknown. The Merck Manual, 944-952 (17th ed. 1999). Transformation
to malignancy typically occurs in a single cell through two or more steps
with subsequent proliferation and clonal expansion. In some leukemias,
specific chromosomal translocations have been identified with consistent
leukemic cell morphology and special clinical features (e.g.,
translocations of 9 and 22 in chronic myelocytic leukemia, and of 15 and
17 in acute promyelocytic leukemia). Acute leukemias are predominantly
undifferentiated cell populations and chronic leukemias more mature cell
forms.

[0011] Acute leukemias are divided into lymphoblastic (ALL) and
non-lymphoblastic (ANLL) types. The Merck Manual, 946-949 (17th ed.
1999). They may be further subdivided by their morphologic and
cytochemical appearance according to the French-American-British (FAB)
classification or according to their type and degree of differentiation.
The use of specific B- and T-cell and myeloid-antigen monoclonal
antibodies are most helpful for classification. ALL is predominantly a
childhood disease which is established by laboratory findings and bone
marrow examination. ANLL, also known as acute myelogenous leukemia or
acute myeloblastic leukemia (AML), occurs at all ages and is the more
common acute leukemia among adults; it is the form usually associated
with irradiation as a causative agent.

[0012] Chronic leukemias are described as being lymphocytic (CLL) or
myelocytic (CML). The Merck Manual, 949-952 (17th ed. 1999). CLL is
characterized by the appearance of mature lymphocytes in blood, bone
marrow, and lymphoid organs. The hallmark of CLL is sustained, absolute
lymphocytosis (>5,000/μL) and an increase of lymphocytes in the
bone marrow. Most CLL patients also have clonal expansion of lymphocytes
with B-cell characteristics. CLL is a disease of middle or old age. In
CML, the characteristic feature is the predominance of granulocytic cells
of all stages of differentiation in blood, bone marrow, liver, spleen,
and other organs. In the symptomatic patient at diagnosis, the total
white blood cell (WBC) count is usually about 200,000/μL, but may
reach 1,000,000/μL. CML is relatively easy to diagnose because of the
presence of the Philadelphia chromosome.

[0013] In addition to the acute and chronic categorization, neoplasms are
also categorized based upon the cells giving rise to such disorder into
precursor or peripheral. See e.g., U.S. patent publication no.
2008/0051379, the disclosure of which is incorporated herein by reference
in its entirety. Precursor neoplasms include ALLs and lymphoblastic
lymphomas and occur in lymphocytes before they have differentiated into
either a T- or B-cell. Peripheral neoplasms are those that occur in
lymphocytes that have differentiated into either T- or B-cells. Such
peripheral neoplasms include, but are not limited to, B-cell CLL, B-cell
prolymphocytic leukemia, lymphoplasmacytic lymphoma, mantle cell
lymphoma, follicular lymphoma, extranodal marginal zone B-cell lymphoma
of mucosa-associated lymphoid tissue, nodal marginal zone lymphoma,
splenic marginal zone lymphoma, hairy cell leukemia, plasmacytoma,
diffuse large B-cell lymphoma and Burkitt lymphoma. In over 95 percent of
CLL cases, the clonal expansion is of a B cell lineage. See Cancer:
Principles & Practice of Oncology (3rd Edition) (1989) (pp. 1843-1847).
In less than 5 percent of CLL cases, the tumor cells have a T-cell
phenotype. Notwithstanding these classifications, however, the
pathological impairment of normal hematopoiesis is the hallmark of all
leukemias.

[0014] Multiple myeloma (MM) is a cancer of plasma cells in the bone
marrow. Normally, plasma cells produce antibodies and play a key role in
immune function. However, uncontrolled growth of these cells leads to
bone pain and fractures, anemia, infections, and other complications.
Multiple myeloma is the second most common hematological malignancy,
although the exact causes of multiple myeloma remain unknown. Multiple
myeloma causes high levels of proteins in the blood, urine, and organs,
including but not limited to M-protein and other immunoglobulins
(antibodies), albumin, and beta-2-microglobulin. M-protein, short for
monoclonal protein, also known as paraprotein, is a particularly abnormal
protein produced by the myeloma plasma cells and can be found in the
blood or urine of almost all patients with multiple myeloma.

[0015] Skeletal symptoms, including bone pain, are among the most
clinically significant symptoms of multiple myeloma. Malignant plasma
cells release osteoclast stimulating factors (including IL-1, IL-6 and
TNF) which cause calcium to be leached from bones causing lytic lesions;
hypercalcemia is another symptom. The osteoclast stimulating factors,
also referred to as cytokines, may prevent apoptosis, or death of myeloma
cells. Fifty percent of patients have radiologically detectable
myeloma-related skeletal lesions at diagnosis. Other common clinical
symptoms for multiple myeloma include polyneuropathy, anemia,
hyperviscosity, infections, and renal insufficiency.

[0016] Solid tumors are abnormal masses of tissue that may, but usually do
not contain cysts or liquid areas. Solid tumors may be benign (not
cancer), or malignant (cancer). Different types of solid tumors are named
for the type of cells that form them. Examples of types solid tumors
include, but are not limited to malignant melanoma, adrenal carcinoma,
breast carcinoma, renal cell cancer, carcinoma of the pancreas,
non-small-cell lung carcinoma (NSCLC) and carcinoma of unknown primary.
Drugs commonly administered to patients with various types or stages of
solid tumors include, but are not limited to, celebrex, etoposide,
cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF,
or a combination thereof.

[0017] While patients who achieve a complete remission after initial
therapy have a good chance for cure, less than 10% of those who do not
respond or relapse achieve a cure or a response lasting longer than 3
years. See Cerny T, et al., Ann Oncol 2002; 13 Suppl 4:211-216.

[0018] Rituximab is known to deplete normal host B cells. See M. Aklilu et
al., Annals of Oncology 15:1109-1114, 2004. The long-term immunologic
effects of B cell depletion with rituximab and the characteristics of the
reconstituting B cell pool in lymphoma patients are not well defined,
despite the widespread usage of this therapy. See Jennifer H. Anolik et
al., Clinical Immunology, vol. 122, issue 2, February 2007, pages
139-145.

[0019] The approach for patients with relapsed or refractory disease
relies heavily on experimental treatments followed by stem cell
transplantation, which may not be appropriate for patients with a poor
performance status or advanced age. Therefore, a tremendous demand exists
for new methods that can be used to treat patients with NHL.

[0022] AMP-activated protein kinase (AMPK) functions as a metabolic check
point which tumor cells must overcome in order to proliferate. Id.
Several mutations have been idenitifed which suppress AMPK signaling in
tumor cells. See Shackelford, D. B. & Shaw, R. J., Nature Rev. Cancer,
2009, 9: 563-575. STK11 has been identified as a tumor suppressor gene
related to the role of AMPK. See Cairns, R. A., et al. Nature Rev., 2011,
11:85-95.

[0023] The transcription factor p53, a tumor suppressor, also has an
important role in the regulation of cellular metabolism. Id. The loss of
p53 in tumor cells may be a significant contributor to changes in tumor
cell metabolism to the glycolytic pathway. Id. The OCT1 transcription
factor, another potential target for chemotherapeutics, may cooperate
with p53 in regulating tumor cell metabolism. Id.

[0024] Pyruvate kinate M2 (PKM2) promotes changes in cellular metabolism
which confer metabolic advantages to cancer cells by supporting cell
proliferation. Id. For example, lung cancer cells which express PKM2 over
PKM1 have been found to have such an advantage. Id. In the clinic, PKM2
has been identified as being overexpressed in a number of cancer types.
Id. Thus PKM2 may be a useful biomarker for the early detection of
tumors.

[0026] The incidence of cancer continues to climb as the general
population ages, as new cancers develop, and as susceptible populations
(e.g., people infected with AIDS, the elderly or excessively exposed to
sunlight) grow. A tremendous demand therefore exists for new methods,
treatments and compositions that can be used to treat patients with
cancer including but not limited to those with lymphoma, NHL, multiple
myeloma, AML, leukemias, and solid tumors.

[0027] Accordingly, compounds that can control and/or inhibit unwanted
angiogenesis or inhibit the production of certain cytokines, including
TNF-α, may be useful in the treatment and prevention of various
forms of cancer.

2.2 Methods of Treating Cancer

[0028] Current cancer therapy may involve surgery, chemotherapy, hormonal
therapy and/or radiation treatment to eradicate neoplastic cells in a
patient (see, for example, Stockdale, 1998, Medicine, vol. 3, Rubenstein
and Federman, eds., Chapter 12, Section IV). Recently, cancer therapy
could also involve biological therapy or immunotherapy. All of these
approaches may pose significant drawbacks for the patient. Surgery, for
example, may be contraindicated due to the health of a patient or may be
unacceptable to the patient. Additionally, surgery may not completely
remove neoplastic tissue. Radiation therapy is only effective when the
neoplastic tissue exhibits a higher sensitivity to radiation than normal
tissue. Radiation therapy can also often elicit serious side effects.
Hormonal therapy is rarely given as a single agent. Although hormonal
therapy can be effective, it is often used to prevent or delay recurrence
of cancer after other treatments have removed the majority of cancer
cells. Certain biological and other therapies are limited in number and
may produce side effects such as rashes or swellings, flu-like symptoms,
including fever, chills and fatigue, digestive tract problems or allergic
reactions.

[0029] With respect to chemotherapy, there are a variety of
chemotherapeutic agents available for treatment of cancer. A number of
cancer chemotherapeutics act by inhibiting DNA synthesis, either directly
or indirectly by inhibiting the biosynthesis of deoxyribonucleotide
triphosphate precursors, to prevent DNA replication and concomitant cell
division. Gilman et al., Goodman and Gilman's: The Pharmacological Basis
of Therapeutics, Tenth Ed. (McGraw Hill, New York).

[0030] Despite availability of a variety of chemotherapeutic agents,
chemotherapy has many drawbacks. Stockdale, Medicine, vol. 3, Rubenstein
and Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeutic
agents are toxic, and chemotherapy causes significant and often dangerous
side effects including severe nausea, bone marrow depression, and
immunosuppression. Additionally, even with administration of combinations
of chemotherapeutic agents, many tumor cells are resistant or develop
resistance to the chemotherapeutic agents. In fact, those cells resistant
to the particular chemotherapeutic agents used in the treatment protocol
often prove to be resistant to other drugs, even if those agents act by
different mechanism from those of the drugs used in the specific
treatment. This phenomenon is referred to as multidrug resistance.
Because of the drug resistance, many cancers prove refractory to standard
chemotherapeutic treatment protocols.

[0031] There exists a significant need for safe and effective methods of
treating, preventing and managing cancer, particularly for cancers that
are refractory to standard treatments, such as surgery, radiation
therapy, chemotherapy and hormonal therapy, while reducing or avoiding
the toxicities and/or side effects associated with the conventional
therapies.

2.3 Cereblon

[0032] The protein Cereblon (CRBN) is a 442-amino acid protein conserved
from plant to human. In humans, the CRBN gene has been identified as a
candidate gene of an autosomal recessive nonsyndromic mental retardation
(ARNSMR). See Higgins, J. J. et al., Neurology, 2004, 63:1927-1931. CRBN
was initially characterized as an RGS-containing novel protein that
interacted with a calcium-activated potassium channel protein (SLO1) in
the rat brain, and was later shown to interact with a voltage-gated
chloride channel (CIC-2) in the retina with AMPK7 and DDB1. See Jo, S. et
al., J. Neurochem, 2005, 94:1212-1224; Hohberger B. et al., FEBS Lett,
2009, 583:633-637; Angers S. et al., Nature, 2006, 443:590-593. DDB1 was
originally identified as a nucleotide excision repair protein that
associates with damaged DNA binding protein 2 (DDB2). Its defective
activity causes the repair defect in the patients with xeroderma
pigmentosum complementation group E (XPE). DDB1 also appears to function
as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3
ubiquitin-protein ligase complexes which mediate the ubiquitination and
subsequent proteasomal degradation of target proteins. CRBN has also been
identified as a target for the development of therapeutic agents for
diseases of the cerebral cortex. See WO 2010/137547 A1.

[0033] Cereblon has recently been identified as a key molecular target
that binds to thalidomide to cause birth defects. See Ito, T. et al.,
Science, 2010, 327:1345-1350. DDB1 was found to interact with CRBN and,
thus, was indirectly associated with thalidomide. Moreover, thalidomide
was able to inhibit auto-ubiquitination of CRBN in vitro, suggesting that
thalidomide is an E3 ubiquitin-ligase inhibitor. Importantly, this
activity was inhibited by thalidomide in wild-type cells, but not in
cells with mutated CRBN binding sites that prevent thalidomide binding.
The thalidomide binding site was mapped to a highly conserved C-terminal
104 amino acid region in CRBN. Individual point mutants in CRBN, Y384A
and W386A were both defective for thalidomide binding, with the double
point mutant having the lowest thalidomide-binding activity. A link
between CRBN and the teratogenic effect of thalidomide was confirmed in
animal models of zebra-fish and chick embryos. Understanding thalidomide
and other drug targets will allow the definition of the molecular
mechanisms of efficacy and/or toxicity and may lead to drugs with
improved efficacy and toxicity profiles.

3. SUMMARY OF THE INVENTION

[0034] Provided herein are methods of treating and preventing cancer,
including primary and metastatic cancer, as well as cancer that is
refractory or resistant to conventional chemotherapy, which comprise
administering to a patient in need of such treatment or prevention a
therapeutically or prophylactically effective amount of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,
having the structure of Formula I:

##STR00001##

or an enantiomer or a mixture of enantiomers thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof as a single agent or as a part of a
combination therapy.

[0035] Also provided herein are methods of managing cancer (e.g.,
preventing its recurrence, or lengthening the time of remission), which
comprise administering to a patient in need of such management a
therapeutically or prophylactically effective amount of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or an
enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof.

[0036] Further provided herein are methods of treating, preventing, or
managing cancer, comprising administering to a patient in need of such
treatment, prevention, or management a therapeutically or
prophylactically effective amount of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or an
enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof; in combination with a therapy conventionally used to treat,
prevent, or manage cancer. Examples of such conventional therapies
include, but are not limited to, surgery, chemotherapy, radiation
therapy, hormonal therapy, biological therapy, and immunotherapy.

[0037] Provided herein is a method for treating, preventing, or managing
cancer, comprising administering to a patient in need of such treatment,
prevention, or management
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or an
enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof, in an amount that is sufficient to provide a plasma
concentration of the compound at steady state, of about 0.001 to about
100 μM. In another embodiment, the amount is sufficient to provide a
peak plasma concentration of the compound at steady state, of about 0.001
to about 100 μM. In another embodiment, the amount is sufficient to
provide a trough plasma concentration of the compound at steady state, of
about 0.01 to about 100 μM. In another embodiment, the amount is
sufficient to provide an area under the curve (AUC) of the compound,
ranging from about 100 to about 100,000 ng*hr/mL.

[0038] In certain embodiments, provided herein are methods for the
treatment or management of lymphoma, multiple myeloma, leukemia, and
solid tumors.

[0041] In some embodiments, the solid tumor is selected from the group
consisting of melanoma, head and neck tumors, breast carcinoma, non-small
cell lung carcinoma, ovarian carcinoma, pancreatic carcinoma, prostate
carcinoma, colorectal carcinoma, and hepatocellular carcinoma.

[0042] In some embodiments, provided herein are methods for the treatment
or management of non-Hodgkin's lymphomas, including but not limited to,
diffuse large B-cell lymphoma (DLBCL), using prognostic factors.

[0043] In some embodiments, provided herein are methods for the use of
gene and protein biomarkers as a predictor of clinical sensitivity to
lymphoma, non-Hodgkin's lymphoma, multiple myeloma, leukemia, AML, and/or
solid tumors and patient response to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or an
enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof.

[0044] The methods provided herein encompass methods for screening or
identifying cancer patients, e.g., lymphoma, non-Hodgkin's lymphoma,
multiple myeloma, leukemia, AML, and solid tumor patients, for treatment
with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,
or an enantiomer or a mixture of enantiomers thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof. In particular, provided herein are
methods for selecting patients having a higher response rate to therapy
with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

[0045] In one embodiment, provided herein is a method of predicting tumor
response to treatment in a lymphoma, non-Hodgkin's lymphoma, multiple
myeloma, leukemia, AML or solid tumor patient, the method comprising
obtaining tumor tissue from the patient, purifying protein or RNA from
the tumor, and measuring the presence or absence of a biomarker by, e.g.,
protein or gene expression analysis. The expression monitored may be, for
example, mRNA expression or protein expression.

[0046] In certain embodiments, the biomarker is a gene associated with an
activated B-cell phenotype of DLBCL. The genes are selected from the
group consisting of IRF4/MUM1, FOXP1, SPIB, CARD11 and BLIMP/PDRM1. In
one embodiment, the biomarker is NF-κB.

[0047] In one embodiment, the mRNA or protein is purified from the tumor
and the presence or absence of a biomarker is measured by gene or protein
expression analysis. In certain embodiments, the presence or absence of a
biomarker is measured by quantitative real-time PCR (QRT-PCR),
microarray, flow cytometry or immunofluorescence. In other embodiments,
the presence or absence of a biomarker is measured by enzyme-linked
immunosorbent assay-based methodologies (ELISA) or other similar methods
known in the art.

[0048] In another embodiment, provided herein is a method of predicting
tumor response to treatment in a non-Hodgkin's lymphoma patient, the
method comprising obtaining tumor cells from the patient, culturing the
cells in the presence or absence of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,
purifying protein or RNA from the cultured cells, and measuring the
presence or absence of a biomarker by, e.g., protein or gene expression
analysis. The expression monitored may be, for example, mRNA expression
or protein expression.

[0049] In another embodiment, provided herein is a method of monitoring
tumor response to
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
treatment in a lymphoma, non-Hodgkin's lymphoma, multiple myeloma,
leukemia, AML or solid tumor patient. The method comprises obtaining a
biological sample from the patient, measuring the expression of a
biomarker in the biological sample, administering
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione to the
patient, thereafter obtaining a second biological sample from the
patient, measuring biomarker expression in the second biological sample,
and comparing the levels of expression, where an increased level of
biomarker expression after treatment indicates the likelihood of an
effective tumor response. In one embodiment, a decreased level of
biomarker expression after treatment indicates the likelihood of
effective tumor response. The biomarker expression monitored can be, for
example, mRNA expression or protein expression. The expression in the
treated sample can increase, for example, by about 1.5×,
2.0×, 3×, 5×, or more.

[0050] In yet another embodiment, a method for monitoring patient
compliance with a drug treatment protocol is provided. The method
comprises obtaining a biological sample from the patient, measuring the
expression level of at least one biomarker in the sample, and determining
if the expression level is increased or decreased in the patient sample
compared to the expression level in a control untreated sample, wherein
an increased or decreased expression indicates patient compliance with
the drug treatment protocol. In one embodiment, the expression of one or
more biomarkers is increased. The biomarker expression monitored can be,
for example, mRNA expression or protein expression. The expression in the
treated sample can increase, for example, by about 1.5×,
2.0×, 3×, 5×, or more.

[0051] In another embodiment, provided herein is a method of predicting
the sensitivity to treatment
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione in a
lymphoma, non-Hodgkin's lymphoma, multiple myeloma, leukemia, AML or
solid tumor patient. In one embodiment, the patient is a non-Hodgkin's
lymphoma patient, specifically, a DLBCL patient. The method comprises
obtaining a biological sample from the patient, optionally isolating or
purifying mRNA from the biological sample, amplifying the mRNA
transcripts by, e.g., RT-PCR, where a higher baseline level of a specific
biomarker indicates a higher likelihood that the cancer will be sensitive
to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In
certain embodiments, the biomarker is a gene associated with an activated
B-cell phenotype. The genes are selected from the group consisting of
IRF4/MUM1, FOXP1, SPIB, CARD11 and BLIMP/PDRM1.

[0052] Also provided herein are methods for the treatment or management of
cancer with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione using
CRBN as a predictive or prognostic factor. In certain embodiments,
provided herein are methods for screening or identifying cancer patients
for treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione using
CRBN levels as a predictive or prognostic factor. In some embodiments,
provided herein are methods for selecting patients having a higher
response rate to therapy with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione using
CRBN levels as a predictive or prognostic factor.

[0053] In one embodiment, provided herein is a method of predicting
patient response to treatment of cancer with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, the
method comprising obtaining biological material from the patient, and
measuring the presence or absence of CRBN.

[0054] In one embodiment, the method comprises obtaining cancer cells from
the patient, culturing the cells in the presence or absence of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,
purifying protein or RNA from the cultured cells, and measuring the
presence or absence of a biomarker by, e.g., protein or gene expression
analysis. The expression monitored may be, for example, mRNA expression
or protein expression. In one embodiment, the cancer is lymphoma,
leukemia, multiple myeloma, solid tumor, non-Hodgkin's lymphoma or
melanoma.

[0055] In another embodiment, provided herein is a method of monitoring
tumor response to drug treatment in a cancer patient. The method
comprises obtaining a biological sample from the patient, measuring the
expression of a biomarker in the biological sample, administering one or
more drugs to the patient, thereafter obtaining a second biological
sample from the patient, measuring biomarker expression in the second
biological sample, and comparing the levels of expression, where an
increased level of biomarker expression after treatment indicates the
likelihood of an effective tumor response. In one embodiment, the cancer
patient is a lymphoma, leukemia, multiple myeloma, solid tumor,
non-Hodgkin's lymphoma or melanoma patient.

[0056] In one embodiment, a decreased level of biomarker expression after
treatment indicates the likelihood of effective tumor response. The
biomarker expression monitored can be, for example, mRNA expression or
protein expression. The expression in the treated sample can increase,
for example, by about 1.5×, 2.0×, 3×, 5×, or
more. In one embodiment, the tumor is a lymphoma, leukemia, multiple
myeloma, solid tumor, non-Hodgkin's lymphoma or melanoma.

[0057] In another embodiment, provided herein is a method of predicting
the sensitivity to drug treatment in a cancer patient, specifically, a
multiple myeloma or non-Hodgkin's lymphoma patient. The method comprises
obtaining a biological sample from the patient, optionally isolating or
purifying mRNA from the biological sample, amplifying the mRNA
transcripts by, e.g., RT-PCR, where a higher baseline level of a specific
biomarker indicates a higher likelihood that the cancer will be sensitive
to treatment with a drug. In certain embodiments, the biomarker is a gene
or protein associated with multiple myeloma or non-Hodgkin's lymphoma. In
one embodiment, the genes are those associated with CRBN and are selected
from the group consisting of DDB1, DDB2, GSK3B, CUL4A, CUL4B, XBP-1,
FAS1, RANBP6, DUS3L, PHGDH, AMPK, IRF4 and NFκB. In another
embodiment, the genes are selected from the group consisting of DDB1,
DDB2, IRF4 and NFκB.

[0058] In one embodiment, identifying a patient having lymphoma, leukemia,
multiple myeloma, a solid tumor, non-Hodgkin's lymphoma, diffuse large
B-cell lymphoma or melanoma sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
identification of a gene or protein associated with CRBN wherein the
presence of the gene or protein associated with CRBN is indicative of
lymphoma, leukemia, multiple myeloma, a solid tumor, non-Hodgkin's
lymphoma, diffuse large B-cell lymphoma or melanoma sensitive to
treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In
one embodiment, the gene or protein associated with CRBN is selected from
the group consisting of DDB1, DDB2, IRF4 and NFκB.

[0059] In one embodiment, identifying a patient having lymphoma, leukemia,
multiple myeloma, a solid tumor, non-Hodgkin's lymphoma or melanoma
sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
comprises measuring the level of CRBN activity in the patient. In another
embodiment, measuring the level of CRBN activity in the patient comprises
measuring DDB1, DDB2, IRF4 and/or NFκB in cells obtained from the
patient.

[0060] In one embodiment, provided herein is a method for treating or
managing non-Hodgkin's lymphoma, comprising:

[0061] (i) identifying a patient having lymphoma, non-Hodgkin's lymphoma,
multiple myeloma, leukemia, AML or a solid tumor sensitive to treatment
with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
and

[0062] (ii) administering to the patient a therapeutically effective
amount of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-di-
one, or a pharmaceutically acceptable salt or solvate (e.g., hydrate)
thereof.

[0063] In one embodiment, the patient has non-Hodgkin's lymphoma. In one
embodiment, the non-Hodgkin's lymphoma is diffuse large B-cell lymphoma.
In another embodiment, the non-Hodgkin's lymphoma is of the activated
B-cell phenotype.

[0064] In one embodiment, identifying a patient having non-Hodgkin's
lymphoma sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
comprises identification of a gene associated with the activated B-cell
phenotype. In one embodiment, the gene associated with the activated
B-cell phenotype is selected from the group consisting of IRF4/MUM1,
FOXP1, SPIB, CARD11 and BLIMP/PDRM1.

[0065] In one embodiment, identifying a patient having non-Hodgkin's
lymphoma sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
comprises measuring the level of NF-κB activity in the patient. In
another embodiment, measuring the level of NF-κB activity in the
patient comprises measuring the baseline NF-κB activity level in
tumor cells obtained from the patient.

[0066] Also provided herein are kits useful for predicting the likelihood
of an effective lymphoma, non-Hodgkin's lymphoma, multiple myeloma,
leukemia, AML or solid tumor treatment or for monitoring the
effectiveness of a treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. The
kit comprises a solid support, and a means for detecting the protein
expression of at least one biomarker in a biological sample. Such a kit
may employ, for example, a dipstick, a membrane, a chip, a disk, a test
strip, a filter, a microsphere, a slide, a multiwell plate, or an optical
fiber. The solid support of the kit can be, for example, a plastic,
silicon, a metal, a resin, glass, a membrane, a particle, a precipitate,
a gel, a polymer, a sheet, a sphere, a polysaccharide, a capillary, a
film, a plate, or a slide. The biological sample can be, for example, a
cell culture, a cell line, a tissue, an oral tissue, gastrointestinal
tissue, an organ, an organelle, a biological fluid, a blood sample, a
urine sample, or a skin sample. The biological sample can be, for
example, a lymph node biopsy, a bone marrow biopsy, or a sample of
peripheral blood tumor cells.

[0067] In an additional embodiment, provided herein is a kit useful for
predicting the likelihood of an effective treatment or for monitoring the
effectiveness of a treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. The
kit comprises a solid support, nucleic acids contacting the support,
where the nucleic acids are complementary to at least 20, 50, 100, 200,
350, or more bases of mRNA, and a means for detecting the expression of
the mRNA in a biological sample.

[0068] In another embodiment, provided herein is a kit useful for
predicting the likelihood of an effective treatment or for monitoring the
effectiveness of a treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. The
kit comprises a solid support, at least one nucleic acid contacting the
support, where the nucleic acid is complementary to at least 20, 50, 100,
200, 350, 500, or more bases of mRNA, and a means for detecting the
expression of the mRNA in a biological sample.

[0069] In certain embodiments, the kits provided herein employ means for
detecting the expression of a biomarker by quantitative real-time PCR
(QRT-PCR), microarray, flow cytometry or immunofluorescence. In other
embodiments, the expression of the biomarker is measured by ELISA-based
methodologies or other similar methods known in the art.

[0070] Also provided herein are pharmaceutical compositions comprising
about 1 to 1,000 mg of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or an
enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof.

[0071] Further provided herein are pharmaceutical compositions comprising
about 1 to 1,000 mg of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or an
enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof; and one or more additional active ingredient. In certain
embodiments, the one or more additional active ingredients are selected
from oblimersen, melphalan, G-CSF, GM-CSF, EPO, a cox-2 inhibitor,
topotecan, pentoxifylline, ciprofloxacin, taxotere, iritotecan,
dexamethasone, doxorubicin, vincristine, IL 2, IFN, dacarbazine, Ara-C,
vinorelbine and isotretinoin.

[0072] Also provided herein are kits useful for predicting the likelihood
of an effective lymphoma, leukemia, multiple myeloma, a solid tumor,
non-Hodgkin's lymphoma, diffuse large B-cell lymphoma or melanoma
treatment or for monitoring the effectiveness of a treatment with one or
more drugs, e.g.,
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. The
kit comprises a solid support, and a means for detecting the protein
expression of at least one biomarker in a biological sample. Such a kit
may employ, for example, a dipstick, a membrane, a chip, a disk, a test
strip, a filter, a microsphere, a slide, a multiwell plate, or an optical
fiber. The solid support of the kit can be, for example, a plastic,
silicon, a metal, a resin, glass, a membrane, a particle, a precipitate,
a gel, a polymer, a sheet, a sphere, a polysaccharide, a capillary, a
film, a plate, or a slide. The biological sample can be, for example, a
cell culture, a cell line, a tissue, an oral tissue, gastrointestinal
tissue, an organ, an organelle, a biological fluid, a blood sample, a
urine sample, or a skin sample. The biological sample can be, for
example, a lymph node biopsy, a bone marrow biopsy, or a sample of
peripheral blood tumor cells.

[0073] In another embodiment, the kit comprises a solid support, nucleic
acids contacting the support, where the nucleic acids are complementary
to at least 20, 50, 100, 200, 350, or more bases of mRNA, and a means for
detecting the expression of the mRNA in a biological sample.

[0074] In certain embodiments, the kits provided herein employ means for
detecting the expression of a biomarker by quantitative real-time PCR
(QRT-PCR), microarray, flow cytometry or immunofluorescence. In other
embodiments, the expression of the biomarker is measured by ELISA-based
methodologies or other similar methods known in the art.

[0092] Provided herein are methods of treating, managing, or preventing
cancer, which comprise administering to a patient in need of such
treatment, management, or prevention a therapeutically or
prophylactically effective amount of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or an
enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof as a single agent or as a part of a combination therapy.

[0093] In certain embodiments,
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or an
enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof, is administered in combination with one or more additional drugs
(or "second active agents") for use in the treatment, management, or
prevention of cancer. Second active agents include small molecules and
large molecules (e.g., proteins and antibodies), some examples of which
are provided herein, as well as stem cells. Methods or therapies, that
can be used in combination with the administration of the compound
provided herein include, but are not limited to, surgery, blood
transfusions, immunotherapy, biological therapy, radiation therapy, and
other non-drug based therapies presently used to treat, prevent or manage
cancer. In certain embodiments, the compound provided herein may be used
as a vaccine adjuvant.

[0094] In some embodiments, the methods provided herein are based, in
part, on the discovery that the expression of certain genes or proteins
associated with certain cancer cells may be utilized as biomarkers to
indicate the effectiveness or progress of a disease treatment. Such
cancers include, but are not limited to, lymphoma, non-Hodgkin's
lymphoma, multiple myeloma, leukemia, acute myeloid leukemia (AML), and
solid tumors. In certain embodiments, the cancer is of the activated
B-cell phenotype in non-Hodgkin's lymphoma. In particular, these
biomarkers can be used to predict, assess and track the effectiveness of
patient treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

[0095] In some embodiments, the methods provided herein are based, in
part, on the discovery that cereblon (CRBN) is associated with the
anti-proliferative activities of certain drugs, such as
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In
some embodiments, CRBN may be utilized as a biomarker to indicate the
effectiveness or progress of a disease treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
Without being bound by a particular theory, CRBN binding may contribute
to or even be required for anti-proliferative or other activities of
certain compounds, such as
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione

[0096] Without being limited to a particular theory,
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione can
mediate growth inhibition, apoptosis and inhibition of angiogenic factors
in certain types of cancer such as lymphoma, non-Hodkin's lymphoma,
multiple myeloma, leukemia, AML, and solid tumors. Upon examining the
expression of several cancer-related genes in several cell types before
and after the treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, it
was discovered that the expression levels of several cancer-related genes
or proteins can be used as biomarkers for predicting and monitoring
cancer treatments.

[0097] It was also discovered that the level of NF-κB activity is
elevated in cells of the activated B-cell phenotype in non-Hodkin's
lymphoma relative to other types of lymphoma cells, and that such cells
may be sensitive to
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
treatment. This suggests that the baseline activity of NF-κB
activity in lymphoma cells may be a predictive biomarker for
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
treatment in non-Hodgkin's lymphoma patients.

[0098] Therefore, in certain embodiments, provided herein are methods for
predicting tumor response to treatment in a non-Hodgkin's lymphoma
patient. In one embodiment, provided herein is a method of predicting
tumor response to treatment in a non-Hodgkin's lymphoma patient, the
method comprising obtaining tumor tissue from the patient, purifying
protein or RNA from the tumor, and measuring the presence or absence of a
biomarker by, e.g., protein or gene expression analysis. The expression
monitored may be, for example, mRNA expression or protein expression. In
certain embodiments, the biomarker is a gene associated with an activated
B-cell phenotype of DLBCL. The genes are selected from the group
consisting of IRF4/MUM1, FOXP1, SPIB, CARD11 and BLIMP/PDRM1. In one
embodiment, the biomarker is NF-κB.

[0099] In another embodiment, the method comprises obtaining tumor cells
from the patient, culturing the cells in the presence or absence of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,
purifying RNA or protein from the cultured cells, and measuring the
presence or absence of a biomarker by, e.g., gene or protein expression
analysis.

[0100] In certain embodiments, the presence or absence of a biomarker is
measured by quantitative real-time PCR (QRT-PCR), microarray, flow
cytometry or immunofluorescence. In other embodiments, the presence or
absence of a biomarker is measured by ELISA-based methodologies or other
similar methods known in the art.

[0101] The methods provided herein encompass methods for screening or
identifying cancer patients, e.g., non-Hodgkin's lymphoma patients, for
treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In
particular, provided herein are methods for selecting patients having, or
who are likely to have, a higher response rate to a therapy with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

[0102] In one embodiment, the method comprises the identification of
patients likely to respond to therapy by obtaining tumor cells from the
patient, culturing the cells in the presence or absence of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,
purifying RNA or protein from the cultured cells, and measuring the
presence or absence of a specific biomarker. The expression monitored can
be, for example, mRNA expression or protein expression. The expression in
the treated sample can increase, or in some cases, decrease, for example,
by about 1.5×, 2.0×, 3×, 5×, or more. In certain
embodiments, the biomarker is a gene associated with an activated B-cell
phenotype. The genes are selected from the group consisting of IRF4/MUM1,
FOXP1, SPIB, CARD11 and BLIMP/PDRM1. In one embodiment, the biomarker is
NF-κB. Baseline levels of expression of these genes can be
predictive of the sensitivity of a cancer to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

[0103] In one embodiment, IRF4/MUM1 expression in cancer cells, e.g.,
ABC-subtype lymphoma, can be decreased with the treatment of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In
some embodiments, IRF4 downregulation by
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione can be
a potential pharmacodynamic biomarker.

[0104] In another embodiment, provided herein is a method of monitoring
tumor response to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione in a
lymphoma, non-Hodgkin's lymphoma, multiple myeloma, leukemia, AML or a
solid tumor patient. The method comprises obtaining a biological sample
from the patient, measuring the expression of one or more biomarkers in
the biological sample, administering
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione to the
patient, thereafter obtaining a second biological sample from the
patient, measuring biomarker expression in the second biological sample,
and comparing the levels of biomarker expression, where an increased
level of biomarker expression after treatment indicates the likelihood of
an effective tumor response. In one embodiment, a decreased level of
biomarker expression after treatment indicates the likelihood of
effective tumor response. In certain embodiments, the biomarker is a gene
associated with an activated B-cell phenotype of non-Hodgkin's lymphoma.
The genes are selected from the group consisting of IRF4/MUM1, FOXP1,
SPIB, CARD11 and BLIMP/PDRM1. In one embodiment, the biomarker is
NF-κB.

[0105] In certain embodiments, the method comprises measuring the
expression of one or more biomarkers genes associated with an activated
B-cell phenotype. The genes are selected from the group consisting of
IRF4/MUM1, FOXP1, SPIB, CARD11 and BLIMP/PDRM1. The expression monitored
can be, for example, mRNA expression or protein expression. The
expression in the treated sample can increase, for example, by about
1.5×, 2.0×, 3×, 5×, or more.

[0106] In yet another embodiment, a method for monitoring patient
compliance with a drug treatment protocol is provided. The method
comprises obtaining a biological sample from the patient, measuring the
expression level of at least one biomarker in the sample, and determining
if the expression level is increased or decreased in the patient sample
compared to the expression level in a control untreated sample, wherein
an increased or decreased expression indicates patient compliance with
the drug treatment protocol. In one embodiment, the expression of one or
more biomarker is increased. The expression monitored can be, for
example, mRNA expression or protein expression. The expression in the
treated sample can increase, for example, by about 1.5×,
2.0×, 3×, 5×, or more. In certain embodiments, the
biomarker is a gene associated with an activated B-cell phenotype. The
genes are selected from the group consisting of IRF4/MUM1, FOXP1, SPIB,
CARD11 and BLIMP/PDRM1. In one embodiment, the biomarker is NF-κB.

[0107] In another embodiment, a method of predicting the sensitivity to
treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione in a
lymphoma, non-Hodgkin's lymphoma, multiple myeloma, leukemia, AML or a
solid tumor patient is provided. In one embodiment, the patient is a
non-Hodgkin's lymphoma patient, specifically, a DLBCL patient. The method
comprises obtaining a biological sample from the patient, optionally
isolating or purifying mRNA from the biological sample, amplifying the
mRNA transcripts by, e.g., RT-PCR, where a higher baseline level of one
or more specific biomarkers indicates a higher likelihood that the cancer
will be sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In
one embodiment, the biomarker is a gene associated with an activated
B-cell phenotype selected from the group consisting of IRF4/MUM1, FOXP1,
SPIB, CARD11 and BLIMP/PDRM1.

[0108] In another embodiment, the method of predicting sensitivity to
treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione in an
NHL, e.g., a DLBCL patient, comprises obtaining a tumor sample from the
patient, embedding the tumor sample into a paraffin-embedded,
formalin-fixed block, and staining the sample with antibodies to CD20,
CD10, bc1-6, IRF4/MUM1, bc1-2, cyclin D2, and/or FOXP1, as described in
Hans et al., Blood, 2004, 103: 275-282, which is hereby incorporated by
reference in its entirety. In one embodiment, CD10, bc1-6, and IRF4/MUM-1
staining can be used to divide DLBCL into GCB and non-GCB subgroups to
predict an outcome.

[0109] In one embodiment, provided herein is a method for predicting tumor
response to treatment in a non-Hodgkin's lymphoma patient, comprising:

(i) obtaining a biological sample from the patient; (ii) measuring
activity of the NF-κB pathway in the biological sample; and (iii)
comparing the level of NF-κB activity in the biological sample to
that of a biological sample of a non-activated B-cell lymphoma subtype;

[0111] In one embodiment, measuring activity of the NF-κB pathway in
the biological sample comprises measuring the level of NF-κB in the
biological sample.

[0112] In one embodiment, provided herein is a method of monitoring tumor
response to treatment in a non-Hodgkin's lymphoma patient, comprising:

(i) obtaining a biological sample from the patient; (ii) measuring the
level of NF-κB activity in the biological sample; (iii)
administering a therapeutically effective amount of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or a
salt, solvate or hydrate thereof to the patient; (iv) obtaining a second
biological sample from the patient; (v) measuring the level of
NF-κB activity in the second biological sample; and (vi) comparing
the level of NF-κB activity in the first biological sample to that
in the second biological sample;

[0113] wherein a decreased level of NF-κB activity in the second
biological sample relative to the first biological sample indicates a
likelihood of an effective patient tumor response.

[0114] In one embodiment, provided herein is a method for monitoring
patient compliance with a drug treatment protocol in a non-Hodgkin's
lymphoma patient, comprising:

(i) obtaining a biological sample from the patient; (ii) measuring the
level of NF-κB activity in the biological sample; and (iii)
comparing the level of NF-κB activity in the biological sample to a
control untreated sample;

[0115] wherein a decreased level of NF-κB activity in the biological
sample relative to the control indicates patient compliance with the drug
treatment protocol.

[0116] In one embodiment, the non-Hodgkin's lymphoma is diffuse large
B-cell lymphoma.

[0117] In another embodiment, the level of NF-κB activity is
measured by an enzyme-linked immunosorbent assay.

[0118] In one embodiment, provided herein is a method for predicting tumor
response to treatment in a non-Hodgkin's lymphoma patient, comprising:

(i) obtaining a biological sample from the patient; (ii) culturing cells
from the biological sample; (iii) purifying RNA from the cultured cells;
and (iv) identifying increased expression of a gene associated with the
activated B-cell phenotype of non-Hodgkin's lymphoma relative to control
non-activated B-cell phenotype of non-Hodgkin's lymphoma;

[0119] wherein increased expression of a gene associated with the
activated B-cell phenotype of non-Hodgkin's lymphoma indicates a
likelihood of an effective patient tumor response to
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
treatment.

[0120] In one embodiment, increased expression is an increase of about
1.5×, 2.0×, 3×, 5×, or more.

[0121] In one embodiment, the gene associated with the activated B-cell
phenotype is selected from the group consisting of IRF4/MUM1, FOXP1,
SPIB, CARD11 and BLIMP/PDRM1.

[0122] In one embodiment, identifying the expression of a gene associated
with the activated B-cell phenotype of non-Hodgkin's lymphoma is
performed by quantitative real-time PCR.

[0123] Also provided herein is a method for treating or managing
non-Hodgkin's lymphoma, comprising:

[0124] (i) identifying a patient having non-Hodgkin's lymphoma sensitive
to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione; and

[0125] (ii) administering to the patient a therapeutically effective
amount of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-di-
one, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0126] In one embodiment, the non-Hodgkin's lymphoma is diffuse large
B-cell lymphoma.

[0127] In another embodiment, the non-Hodgkin's lymphoma is of the
activated B-cell phenotype.

[0128] In another embodiment, the diffuse large B-cell lymphoma is
characterized by the expression of one or more biomarkers overexpressed
in RIVA, U2932, TMD8, OCI-Ly3 or OCI-Ly10 cell lines.

[0129] In another embodiment, the diffuse large B-cell lymphoma is
characterized by the expression of one or more biomarkers overexpressed
in RIVA, U2932, TMD8 or OCI-Ly10 cell lines.

[0130] In one embodiment, identifying a patient having lymphoma sensitive
to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
comprises characterization of the lymphoma phenotype of the patient.

[0131] In one embodiment, the lymphoma phenotype is characterized as an
activated B-cell subtype.

[0132] In one embodiment, the lymphoma phenotype is characterized as an
activated B-cell subtype of diffuse large B-cell lymphoma.

[0133] In certain embodiments, identification of the lymphoma phenotype
comprises obtaining a biological sample from a patient having lymphoma.
In one embodiment, the biological sample is a cell culture or tissue
sample. In one embodiment, the biological sample is a sample of tumor
cells. In another embodiment, the biological sample is a lymph node
biopsy, a bone marrow biopsy, or a sample of peripheral blood tumor
cells. In one embodiment, the biological sample is a blood sample.

[0134] In one embodiment, identifying a patient having non-Hodgkin's
lymphoma sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
comprises identification of a gene associated with an activated B-cell
phenotype. In one embodiment, the gene associated with the activated
B-cell phenotype is selected from the group consisting of IRF4/MUM1,
FOXP1, SPIB, CARD11 and BLIMP/PDRM1.

[0135] In one embodiment, identifying a patient having non-Hodgkin's
lymphoma sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
comprises measuring the level of NF-κB activity in the patient. In
another embodiment, measuring the level of NF-κB activity in a
patient comprises measuring the baseline NF-κB activity level in
tumor cells obtained from the patient.

[0136] In another embodiment, the diffuse large B-cell lymphoma is
characterized by one or more of the following:

[0137] Additional prognostic factors that may be used concurrently with
those provided herein are prognostic factors of disease (tumor) burden,
absolute lymphocyte count (ALC), time since last rituximab therapy for
lymphomas, or all of the above.

[0138] Also provided herein is a method of selecting a group of cancer
patients based on the level of CRBN expression, or the levels of DDB1,
DDB2, IRF4 or NFκB expression within the cancer, for the purposes
of predicting clinical response, monitoring clinical response, or
monitoring patient compliance to dosing by
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, a
stereoisomer thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof; wherein the cancer
patients are selected from multiple myeloma, non-Hodgkin's lymphoma,
diffuse large B-cell lymphoma, melanoma and solid tumor patients.
Baseline levels of expression of these genes can be predictive of the
sensitivity of a cancer to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

[0139] In one embodiment, IRF4/MUM1 expression in cancer cells, e.g.,
ABC-subtype lymphoma, can be decreased with the treatment of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In
some embodiments, IRF4 downregulation by
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione can be
a potential pharmacodynamic biomarker.

[0140] In one embodiment, the cancer patients are multiple myeloma
patients.

[0141] In one embodiment, the cancer patients are non-Hodgkin's lymphoma
patients.

[0142] In one embodiment, the method of selecting a group of cancer
patients is based on the level of DDB1 expression within the cancer.

[0143] In one embodiment, the method of selecting a group of cancer
patients is based on the level of DDB2 expression within the cancer.

[0144] In one embodiment, the method of selecting a group of cancer
patients is based on the level of IRF4 expression within the cancer.

[0145] In one embodiment, the method of selecting a group of cancer
patients is based on the level of NFκB expression within the
cancer.

[0146] In another embodiment, the method comprises selecting a group of
cancer patients responsive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, a
stereoisomer thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof based on the level
of CRBN expression, or the levels of DDB1, DDB2, IRF4 or NFκB
expression within the patient's T cells, B cells, or plasma cells, for
the purposes of predicting clinical response, monitoring clinical
response, or monitoring patient compliance to dosing by
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, a
stereoisomer thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof.

In one embodiment, the cancer patients are selected from multiple
myeloma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, melanoma
and solid tumor patients.

[0147] Also provided herein are methods of treating cancer, e.g.,
lymphoma, non-Hodgkin's lymphoma, multiple myeloma, leukemia, acute
myeloid leukemia (AML), and solid tumors, which result in an improvement
in overall survival of the patient. In some embodiments, the improvement
in overall survival of the patient is observed in a patient population
sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In
some embodiments, the patient population sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione is
characterized by one or more biomarkers provided herein.

[0148] In other embodiments, provided herein are methods of treating
cancer, e.g., lymphoma, non-Hodgkin's lymphoma, multiple myeloma,
leukemia, acute myeloid leukemia (AML), and solid tumors, which result in
disease free survival of the patient. In some embodiments, disease free
survival of the patient is observed in a patient population sensitive to
treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In
some embodiments, the patient population sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione is
characterized by one or more biomarkers provided herein.

[0149] In other embodiments, provided herein are methods of treating
cancer, e.g., lymphoma, non-Hodgkin's lymphoma, multiple myeloma,
leukemia, acute myeloid leukemia (AML), and solid tumors, which result in
an improvement in the objective response rate in the patient population.
In some embodiments, the patient population sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In
some embodiments, the patient population sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione is
characterized by one or more biomarkers provided herein.

[0150] In other embodiments, provided herein are methods of treating
cancer, e.g., lymphoma, non-lymphoma, Hodgkin's lymphoma, multiple
myeloma, leukemia, acute myeloid leukemia (AML), and solid tumors, which
result in an improved time to progression or progression-free survival of
the patient. In some embodiments, the improved time to progression or
progression-free survival of the patient is observed in a patient
population sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. In
some embodiments, the patient population sensitive to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione is
characterized by one or more biomarkers provided herein.

[0151] Also provided herein are kits useful for predicting the likelihood
of an effective lymphoma, non-Hodgkin's lymphoma, multiple myeloma,
leukemia, AML or solid tumor treatment or for monitoring the
effectiveness of a treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. The
kit comprises a solid support, and a means for detecting the expression
of a biomarker in a biological sample. Such a kit may employ, for
example, a dipstick, a membrane, a chip, a disk, a test strip, a filter,
a microsphere, a slide, a multiwell plate, or an optical fiber. The solid
support of the kit can be, for example, a plastic, silicon, a metal, a
resin, glass, a membrane, a particle, a precipitate, a gel, a polymer, a
sheet, a sphere, a polysaccharide, a capillary, a film, a plate, or a
slide. The biological sample can be, for example, a cell culture, a cell
line, a tissue, an oral tissue, gastrointestinal tissue, an organ, an
organelle, a biological fluid, a blood sample, a urine sample, or a skin
sample. The biological sample can be, for example, a lymph node biopsy, a
bone marrow biopsy, or a sample of peripheral blood tumor cells.

[0152] In one embodiment, the kit comprises a solid support, nucleic acids
contacting the support, where the nucleic acids are complementary to at
least 20, 50, 100, 200, 350, or more bases of mRNA of a gene associated
with an activated B-cell phenotype in a NHL, and a means for detecting
the expression of the mRNA in a biological sample. In one embodiment, the
gene associated with the activated B-cell phenotype is selected from the
group consisting of IRF4/MUM1, FOXP1, SPIB, CARD11 and BLIMP/PDRM1.

[0153] In one embodiment, a kit useful for predicting the likelihood of an
effective lymphoma, non-Hodgkin's lymphoma, multiple myeloma, leukemia,
AML or solid tumor treatment, or for monitoring the effectiveness of a
treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione is
provided. The kit comprises a solid support, and a means for detecting
the expression of NF-κB in a biological sample. In one embodiment,
the biological sample is a cell culture or tissue sample. In one
embodiment, the biological sample is a sample of tumor cells. In another
embodiment, the biological sample is a lymph node biopsy, a bone marrow
biopsy, or a sample of peripheral blood tumor cells. In one embodiment,
the biological sample is a blood sample. In one embodiment, the NHL is
DLBCL.

[0154] In certain embodiments, the kits provided herein employ means for
detecting the expression of a biomarker by quantitative real-time PCR
(QT-PCR), microarray, flow cytometry or immunofluorescence. In other
embodiments, the expression of the biomarker is measured by ELISA-based
methodologies or other similar methods known in the art. Additional mRNA
and protein expression techniques may be used in connection with the
methods and kits provided herein, e.g., cDNA hybridization and cytometric
bead array methods.

[0155] In one embodiment, provided herein is a kit for predicting tumor
response to treatment with
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione in a
non-Hodgkin's lymphoma patient, comprising:

(i) a solid support; and (ii) a means for detecting the expression of a
biomarker of an activated B-cell phenotype of non-Hodgkin's lymphoma in a
biological sample.

[0156] In one embodiment, the biomarker is NF-κB.

[0157] In one embodiment, the biomarker is a gene associated with the
activated B-cell phenotype and is selected from the group consisting of
IRF4/MUM1, FOXP1, SPIB, CARD11 and BLIMP/PDRM1.

[0158] In particular methods of the invention, a
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione is
administered in combination with a therapy conventionally used to treat,
prevent or manage cancer. Examples of such conventional therapies
include, but are not limited to, surgery, chemotherapy, radiation
therapy, hormonal therapy, biological therapy and immunotherapy.

[0159] Also provided herein are pharmaceutical compositions, single unit
dosage forms, dosing regimens and kits which comprise
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or a
pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,
clathrate, or prodrug thereof, and a second, or additional, active agent.
Second active agents include specific combinations, or "cocktails," of
drugs.

[0160] In some embodiments, the methods for treating, preventing and/or
managing lymphomas provided herein may be used in patients that have not
responded to standard treatment. In one embodiment, the lymphoma is
relapsed, refractory or resistant to conventional therapy.

[0161] In other embodiments, the methods for treating, preventing and/or
managing lymphomas provided herein may be used in treatment naive
patients, i.e., patients that have not yet received treatment.

[0162] In certain embodiments,
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or an
enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof, is administered in combination or alternation with a
therapeutically effective amount of one or more additional active agents.
Second active agents include small molecules and large molecules (e.g.,
proteins and antibodies), examples of which are provided herein, as well
as stem cells. Methods or therapies that can be used in combination with
the administration of the compound provided herein include, but are not
limited to, surgery, blood transfusions, immunotherapy, biological
therapy, radiation therapy, and other non-drug based therapies presently
used to treat, prevent or manage disease and conditions associated with
or characterized by undesired angiogenesis.

[0163] In one embodiment, the additional active agent is selected from the
group consisting of an alkylating agent, an adenosine analog, a
glucocorticoid, a kinase inhibitor, a SYK inhibitor, a PDE3 inhibitor, a
PDE7 inhibitor, doxorubicin, chlorambucil, vincristine, bendamustine,
forskolin, rituximab, or a combination thereof.

[0164] In one embodiment, the additional active agent is rituximab.

[0165] In one embodiment, the glucocorticoid is hydrocortisone or
dexamethasone.

[0166] In one embodiment,
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione is
administered in an amount of about 5 to about 50 mg per day.

[0167] In one embodiment,
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione is
administered in an amount of about 5 to about 25 mg per day.

[0168] In another embodiment,
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione is
administered in an amount of about 5, 10, 15, 25, 30 or 50 mg per day.

[0169] In another embodiment, 10 or 25 mg of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione is
administered per day.

[0170] In one embodiment,
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione is
administered twice per day.

[0171] Provided herein are pharmaceutical compositions (e.g., single unit
dosage forms) that can be used in methods disclosed herein. In certain
embodiments, the pharmaceutical compositions comprise
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or an
enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof, and a second active agent.

[0172] In one embodiment,
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione is
orally administered.

[0173] In one embodiment,
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione is
administered in a capsule or tablet.

[0174] In one embodiment,
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione is
administered for 21 days followed by seven days rest in a 28 day cycle.

5.1 DEFINITIONS

[0175] To facilitate understanding of the disclosure set forth herein, a
number of terms are defined below.

[0176] The term "subject" or "patient" refers to an animal, including, but
not limited to, a mammal, including a primate (e.g., human), cow, sheep,
goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and
"patient" are used interchangeably herein in reference, for example, to a
mammalian subject, such as a human subject.

[0177] As used herein, and unless otherwise specified, the terms "treat,"
"treating" and "treatment" refer to the eradication or amelioration of a
disease or disorder, or of one or more symptoms associated with the
disease or disorder. In certain embodiments, the terms refer to
minimizing the spread or worsening of the disease or disorder resulting
from the administration of one or more prophylactic or therapeutic agents
to a patient with such a disease or disorder. In some embodiments, the
terms refer to the administration of a compound provided herein, with or
without other additional active agent, after the onset of symptoms of the
particular disease.

[0178] As used herein, and unless otherwise specified, the terms
"prevent," "preventing" and "prevention" refer to the prevention of the
onset, recurrence or spread of a disease or disorder, or of one or more
symptoms thereof. In certain embodiments, the terms refer to the
treatment with or administration of a compound provided herein, with or
without other additional active compound, prior to the onset of symptoms,
particularly to patients at risk of diseases or disorders provided
herein. The terms encompass the inhibition or reduction of a symptom of
the particular disease. Patients with familial history of a disease in
particular are candidates for preventive regimens in certain embodiments.
In addition, patients who have a history of recurring symptoms are also
potential candidates for the prevention. In this regard, the term
"prevention" may be interchangeably used with the term "prophylactic
treatment."

[0179] As used herein, and unless otherwise specified, the terms "manage,"
"managing" and "management" refer to preventing or slowing the
progression, spread or worsening of a disease or disorder, or of one or
more symptoms thereof. Often, the beneficial effects that a patient
derives from a prophylactic and/or therapeutic agent do not result in a
cure of the disease or disorder. In this regard, the term "managing"
encompasses treating a patient who had suffered from the particular
disease in an attempt to prevent or minimize the recurrence of the
disease, or lengthening the time during which the remains in remission.

[0180] As used herein, and unless otherwise specified, a "therapeutically
effective amount" of a compound is an amount sufficient to provide a
therapeutic benefit in the treatment or management of a disease or
disorder, or to delay or minimize one or more symptoms associated with
the disease or disorder. A therapeutically effective amount of a compound
means an amount of therapeutic agent, alone or in combination with other
therapies, which provides a therapeutic benefit in the treatment or
management of the disease or disorder. The term "therapeutically
effective amount" can encompass an amount that improves overall therapy,
reduces or avoids symptoms or causes of disease or disorder, or enhances
the therapeutic efficacy of another therapeutic agent.

[0181] As used herein, and unless otherwise specified, a "prophylactically
effective amount" of a compound is an amount sufficient to prevent a
disease or disorder, or prevent its recurrence. A prophylactically
effective amount of a compound means an amount of therapeutic agent,
alone or in combination with other agents, which provides a prophylactic
benefit in the prevention of the disease. The term "prophylactically
effective amount" can encompass an amount that improves overall
prophylaxis or enhances the prophylactic efficacy of another prophylactic
agent.

[0182] The term "pharmaceutically acceptable carrier," "pharmaceutically
acceptable excipient," "physiologically acceptable carrier," or
"physiologically acceptable excipient" refers to a
pharmaceutically-acceptable material, composition, or vehicle, such as a
liquid or solid filler, diluent, excipient, solvent, or encapsulating
material. In one embodiment, each component is "pharmaceutically
acceptable" in the sense of being compatible with the other ingredients
of a pharmaceutical formulation, and suitable for use in contact with the
tissue or organ of humans and animals without excessive toxicity,
irritation, allergic response, immunogenicity, or other problems or
complications, commensurate with a reasonable benefit/risk ratio. See,
Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott
Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical
Excipients, 5th Edition; Rowe et al., Eds., The Pharmaceutical Press and
the American Pharmaceutical Association: 2005; and Handbook of
Pharmaceutical Additives, 3rd Edition; Ash and Ash Eds., Gower Publishing
Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed.,
CRC Press LLC: Boca Raton, Fla., 2004).

[0183] "Tumor," as used herein, refers to all neoplastic cell growth and
proliferation, whether malignant or benign, and all pre-cancerous and
cancerous cells and tissues. "Neoplastic," as used herein, refers to any
form of dysregulated or unregulated cell growth, whether malignant or
benign, resulting in abnormal tissue growth. Thus, "neoplastic cells"
include malignant and benign cells having dysregulated or unregulated
cell growth.

[0184] The term "relapsed" refers to a situation where a subject or a
mammal, which has had a remission of cancer after therapy has a return of
cancer cells.

[0185] As used herein, an "effective patient tumor response" refers to any
increase in the therapeutic benefit to the patient. An "effective patient
tumor response" can be, for example, a 5%, 10%, 25%, 50%, or 100%
decrease in the rate of progress of the tumor. An "effective patient
tumor response" can be, for example, a 5%, 10%, 25%, 50%, or 100%
decrease in the physical symptoms of a cancer. An "effective patient
tumor response" can also be, for example, a 5%, 10%, 25%, 50%, 100%,
200%, or more increase in the response of the patient, as measured by any
suitable means, such as gene expression, cell counts, assay results, etc.

[0186] The term "likelihood" generally refers to an increase in the
probability of an event. The term "likelihood" when used in reference to
the effectiveness of a patient tumor response generally contemplates an
increased probability that the rate of tumor progress or tumor cell
growth will decrease. The term "likelihood" when used in reference to the
effectiveness of a patient tumor response can also generally mean the
increase of indicators, such as mRNA or protein expression, that may
evidence an increase in the progress in treating the tumor.

[0187] The term "predict" generally means to determine or tell in advance.
When used to "predict" the effectiveness of a cancer treatment, for
example, the term "predict" can mean that the likelihood of the outcome
of the cancer treatment can be determined at the outset, before the
treatment has begun, or before the treatment period has progressed
substantially.

[0188] The term "monitor," as used herein, generally refers to the
overseeing, supervision, regulation, watching, tracking, or surveillance
of an activity. For example, the term "monitoring the effectiveness of a
compound" refers to tracking the effectiveness in treating a cancer in a
patient or in a tumor cell culture. Similarly, the "monitoring," when
used in connection with patient compliance, either individually, or in a
clinical trial, refers to the tracking or confirming that the patient is
actually taking the immunomodulatory compound being tested as prescribed.
The monitoring can be performed, for example, by following the expression
of mRNA or protein biomarkers.

[0189] An improvement in the cancer or cancer-related disease can be
characterized as a complete or partial response. "Complete response"
refers to an absence of clinically detectable disease with normalization
of any previously abnormal radiographic studies, bone marrow, and
cerebrospinal fluid (CSF) or abnormal monoclonal protein measurements.
"Partial response" refers to at least about a 10%, 20%, 30%, 40%, 50%,
60%, 70%, 80%, or 90% decrease in all measurable tumor burden (i.e., the
number of malignant cells present in the subject, or the measured bulk of
tumor masses or the quantity of abnormal monoclonal protein) in the
absence of new lesions. The term "treatment" contemplates both a complete
and a partial response.

[0190] The term "refractory or resistant" refers to a circumstance where a
subject or a mammal, even after intensive treatment, has residual cancer
cells in his body.

[0191] The term "drug resistance" refers to the condition when a disease
does not respond to the treatment of a drug or drugs. Drug resistance can
be either intrinsic, which means the disease has never been responsive to
the drug or drugs, or it can be acquired, which means the disease ceases
responding to a drug or drugs that the disease had previously responded
to. In certain embodiments, drug resistance is intrinsic. In certain
embodiments, the drug resistance is acquired.

[0192] The term "sensitivity" and "sensitive" when made in reference to
treatment with compound is a relative term which refers to the degree of
effectiveness of the compound in lessening or decreasing the progress of
a tumor or the disease being treated. For example, the term "increased
sensitivity" when used in reference to treatment of a cell or tumor in
connection with a compound refers to an increase of, at least a 5%, or
more, in the effectiveness of the tumor treatment.

[0193] The term "expressed" or "expression" as used herein refers to the
transcription from a gene to give an RNA nucleic acid molecule at least
complementary in part to a region of one of the two nucleic acid strands
of the gene. The term "expressed" or "expression" as used herein also
refers to the translation from the RNA molecule to give a protein, a
polypeptide or a portion thereof.

[0194] An mRNA that is "upregulated" is generally increased upon a given
treatment or condition. An mRNA that is "downregulated" generally refers
to a decrease in the level of expression of the mRNA in response to a
given treatment or condition. In some situations, the mRNA level can
remain unchanged upon a given treatment or condition.

[0195] An mRNA from a patient sample can be "upregulated" when treated
with an immunomodulatory compound, as compared to a non-treated control.
This upregulation can be, for example, an increase of about 5%, 10%, 20%,
30%, 40%, 50%, 60%, 70%, 90%, 100%, 200%, 300%, 500%, 1,000%, 5,000% or
more of the comparative control mRNA level.

[0196] Alternatively, an mRNA can be "downregulated", or expressed at a
lower level, in response to administration of certain immunomodulatory
compounds or other agents. A downregulated mRNA can be, for example,
present at a level of about 99%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%,
20%, 10%, 1% or less of the comparative control mRNA level.

[0197] Similarly, the level of a polypeptide or protein biomarker from a
patient sample can be increased when treated with an immunomodulatory
compound, as compared to a non-treated control. This increase can be
about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 90%, 100%, 200%, 300%, 500%,
1,000%, 5,000% or more of the comparative control protein level.

[0198] Alternatively, the level of a protein biomarker can be decreased in
response to administration of certain immunomodulatory compounds or other
agents. This decrease can be, for example, present at a level of about
99%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 1% or less of the
comparative control protein level.

[0199] The terms "determining", "measuring", "evaluating", "assessing" and
"assaying" as used herein generally refer to any form of measurement, and
include determining if an element is present or not. These terms include
both quantitative and/or qualitative determinations. Assessing may be
relative or absolute. "Assessing the presence of" can include determining
the amount of something present, as well as determining whether it is
present or absent.

[0201] Compounds that are acidic in nature are capable of forming salts
with various pharmaceutically acceptable bases. The bases that can be
used to prepare pharmaceutically acceptable base addition salts of such
acidic compounds are those that form non-toxic base addition salts, i.e.,
salts containing pharmacologically acceptable cations such as, but not
limited to, alkali metal or alkaline earth metal salts and the calcium,
magnesium, sodium or potassium salts in particular. Suitable organic
bases include, but are not limited to, N,N dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine
(N-methylglucamine), lysine, and procaine.

[0202] As used herein and unless otherwise indicated, the term "solvate"
means a compound provided herein or a salt thereof, that further includes
a stoichiometric or non-stoichiometric amount of solvent bound by
non-covalent intermolecular forces. Where the solvent is water, the
solvate is a hydrate.

[0203] As used herein and unless otherwise indicated, the term "prodrug"
means a derivative of a compound that can hydrolyze, oxidize, or
otherwise react under biological conditions (in vitro or in vivo) to
provide the compound. Examples of prodrugs include, but are not limited
to, derivatives of the compound of Formula I provided herein that
comprise biohydrolyzable moieties such as biohydrolyzable amides,
biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable
carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate
analogues. Other examples of prodrugs include derivatives of the compound
of Formula I provided herein that comprise --NO, --NO2, --ONO, or
--ONO2 moieties. Prodrugs can be prepared using such methods as
described in Burger's Medicinal Chemistry and Drug Discovery, 172-178,
949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design of Prodrugs (H.
Bundgaard ed., Elselvier, N.Y. 1985).

[0204] As used herein and unless otherwise indicated, the terms
"biohydrolyzable amide," "biohydrolyzable ester," "biohydrolyzable
carbamate," "biohydrolyzable carbonate," "biohydrolyzable ureide," and
"biohydrolyzable phosphate" mean an amide, ester, carbamate, carbonate,
ureide, or phosphate, respectively, of a compound that either: 1) does
not interfere with the biological activity of the compound but can confer
upon that compound advantageous properties in vivo, such as uptake,
duration of action, or onset of action; or 2) is biologically inactive
but is converted in vivo to the biologically active compound. Examples of
biohydrolyzable esters include, but are not limited to, lower alkyl
esters, lower acyloxyalkyl esters (such as acetoxylmethyl, acetoxyethyl,
aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters),
lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower
alkoxyacyloxyalkyl esters (such as methoxycarbonyl-oxymethyl,
ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters),
alkoxyalkyl esters, choline esters, and acylamino alkyl esters (such as
acetamidomethyl esters). Examples of biohydrolyzable amides include, but
are not limited to, lower alkyl amides, α-amino acid amides,
alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of
biohydrolyzable carbamates include, but are not limited to, lower
alkylamines, substituted ethylenediamines, amino acids,
hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether
amines.

[0205] As used herein and unless otherwise indicated, the term
"stereomerically pure" means a composition that comprises one
stereoisomer of a compound and is substantially free of other
stereoisomers of that compound. For example, a stereomerically pure
composition of a compound having one chiral center will be substantially
free of the opposite enantiomer of the compound. A stereomerically pure
composition of a compound having two chiral centers will be substantially
free of other diastereomers of the compound. In certain embodiments, a
stereomerically pure compound comprises greater than about 80% by weight
of one stereoisomer of the compound and less than about 20% by weight of
other stereoisomers of the compound, greater than about 90% by weight of
one stereoisomer of the compound and less than about 10% by weight of the
other stereoisomers of the compound, greater than about 95% by weight of
one stereoisomer of the compound and less than about 5% by weight of the
other stereoisomers of the compound, or greater than about 97% by weight
of one stereoisomer of the compound and less than about 3% by weight of
the other stereoisomers of the compound. As used herein and unless
otherwise indicated, the term "stereomerically enriched" means a
composition that comprises greater than about 60% by weight of one
stereoisomer of a compound, greater than about 70% by weight, or greater
than about 80% by weight of one stereoisomer of a compound. As used
herein and unless otherwise indicated, the term "enantiomerically pure"
means a stereomerically pure composition of a compound having one chiral
center. Similarly, the term "stereomerically enriched" means a
stereomerically enriched composition of a compound having one chiral
center.

[0206] The term "about" or "approximately" means an acceptable error for a
particular value as determined by one of ordinary skill in the art, which
depends in part on how the value is measured or determined. In certain
embodiments, the term "about" or "approximately" means within 1, 2, 3, or
4 standard deviations. In certain embodiments, the term "about" or
"approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%,
3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

5.2 CLINICAL TRIALS ENDPOINTS FOR CANCER APPROVAL

[0207] "Overall survival" is defined as the time from randomization until
death from any cause, and is measured in the intent-to-treat population.
Overall survival should be evaluated in randomized controlled studies.
Demonstration of a statistically significant improvement in overall
survival can be considered to be clinically significant if the toxicity
profile is acceptable, and has often supported new drug approval.

[0208] Several endpoints are based on tumor assessments. These endpoints
include disease free survival (DFS), objective response rate (ORR), time
to progression (TTP), progression-free survival (PFS), and
time-to-treatment failure (TTF). The collection and analysis of data on
these time-dependent endpoints are based on indirect assessments,
calculations, and estimates (e.g., tumor measurements).

[0209] Generally, "disease free survival" (DFS) is defined as the time
from randomization until recurrence of tumor or death from any cause.
Although overall survival is a conventional endpoint for most adjuvant
settings, DFS can be an important endpoint in situations where survival
may be prolonged, making a survival endpoint impractical. DFS can be a
surrogate for clinical benefit or it can provide direct evidence of
clinical benefit. This determination is based on the magnitude of the
effect, its risk-benefit relationship, and the disease setting. The
definition of DFS can be complicated, particularly when deaths are noted
without prior tumor progression documentation. These events can be scored
either as disease recurrences or as censored events. Although all methods
for statistical analysis of deaths have some limitations, considering all
deaths (deaths from all causes) as recurrences can minimize bias. DFS can
be overestimated using this definition, especially in patients who die
after a long period without observation. Bias can be introduced if the
frequency of long-term follow-up visits is dissimilar between the study
arms or if dropouts are not random because of toxicity.

[0210] "Objective response rate" (ORR) is defined as the proportion of
patients with tumor size reduction of a predefined amount and for a
minimum time period. Response duration usually is measured from the time
of initial response until documented tumor progression. Generally, the
FDA has defined ORR as the sum of partial responses plus complete
responses. When defined in this manner, ORR is a direct measure of drug
antitumor activity, which can be evaluated in a single-arm study. If
available, standardized criteria should be used to ascertain response. A
variety of response criteria have been considered appropriate (e.g.,
RECIST criteria) (Therasse et al., (2000) J. Natl. Cancer Inst, 92:
205-16). The significance of ORR is assessed by its magnitude and
duration, and the percentage of complete responses (no detectable
evidence of tumor).

[0211] "Time to progression" (TTP) and "progression-free survival" (PFS)
have served as primary endpoints for drug approval. TTP is defined as the
time from randomization until objective tumor progression; TTP does not
include deaths. PFS is defined as the time from randomization until
objective tumor progression or death. Compared with TTP, PFS is the
preferred regulatory endpoint. PFS includes deaths and thus can be a
better correlate to overall survival. PFS assumes patient deaths are
randomly related to tumor progression. However, in situations where the
majority of deaths are unrelated to cancer, TTP can be an acceptable
endpoint.

[0212] As an endpoint to support drug approval, PFS can reflect tumor
growth and be assessed before the determination of a survival benefit.
Its determination is not confounded by subsequent therapy. For a given
sample size, the magnitude of effect on PFS can be larger than the effect
on overall survival. However, the formal validation of PFS as a surrogate
for survival for the many different malignancies that exist can be
difficult. Data are sometimes insufficient to allow a robust evaluation
of the correlation between effects on survival and PFS. Cancer trials are
often small, and proven survival benefits of existing drugs are generally
modest. The role of PFS as an endpoint to support licensing approval
varies in different cancer settings. Whether an improvement in PFS
represents a direct clinical benefit or a surrogate for clinical benefit
depends on the magnitude of the effect and the risk-benefit of the new
treatment compared to available therapies.

[0213] "Time-to-treatment failure" (TTF) is defined as a composite
endpoint measuring time from randomization to discontinuation of
treatment for any reason, including disease progression, treatment
toxicity, and death. TTF is not recommended as a regulatory endpoint for
drug approval. TTF does not adequately distinguish efficacy from these
additional variables. A regulatory endpoint should clearly distinguish
the efficacy of the drug from toxicity, patient or physician withdrawal,
or patient intolerance.

5.3 THE COMPOUND

[0214] The compound suitable for use in the methods provided herein is
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,
having the structure of Formula I:

##STR00002##

or an enantiomer or a mixture of enantiomers thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof.

[0215] The compound of Formula I can be prepared according to the methods
described in the Examples provided herein or as described in U.S. Pat.
No. 7,635,700, the disclosure of which is incorporated herein by
reference in its entirety. The compound can be also synthesized according
to other methods apparent to those of skill in the art based upon the
teaching herein.

[0216] The compound of Formula I markedly inhibits TNF-α,
IL-1β, and other inflammatory cytokines in LPS-stimulated hPBMC and
human whole blood. TNF-α is an inflammatory cytokine produced by
macrophages and monocytes during acute inflammation. TNF-α is
responsible for a diverse range of signaling events within cells.
TNF-α may play a pathological role in cancer. Without being limited
by theory, one of the biological effects exerted by the immunomodulatory
compound of Formula I is the reduction of synthesis of TNF-α. The
immunomodulatory compound of Formula I enhances the degradation of
TNF-α mRNA. The compound of Formula I also potently inhibits
IL-1β and stimulates IL-10 under these conditions.

[0217] Further, without being limited by theory, the compound of Formula I
is a potent co-stimulator of T cells and increase cell proliferation in a
dose dependent manner under appropriate conditions.

[0218] In certain embodiments, without being limited by theory, the
biological effects exerted by the immunomodulatory compound of Formula I
include, but not limited to, anti-angiogenic and immune modulating
effects.

[0219] In certain embodiments, the compound of Formula I is a solid. In
certain embodiments, the compound of Formula I is hydrated. In certain
embodiments, the compound of Formula I is solvated. In certain
embodiments, the compound of Formula I is anhydrous. In certain
embodiments, the compound of Formula I is nonhygroscopic.

[0220] In certain embodiments, the solid compound of Formula I is
amorphous. In certain embodiments, the solid compound of Formula I is
crystalline. In certain embodiments, the solid compound of Formula I is
in a crystalline form described in U.S. Provisional Pat. App. No.
61/451,806, filed Mar. 11, 2011, which is incorporated herein by
reference in its entirety.

[0221] The solid forms of the compound of Formula I can be prepared
according to the methods described in the disclosure of U.S. Provisional
Pat. App. No. 61/451,806. The solid forms can be also prepared according
to other methods apparent to those of skill in the art.

[0222] In certain embodiments, the compound of Formula I is a
hydrochloride salt of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or an
enantiomer or a mixture of enantiomers thereof; or a pharmaceutically
acceptable solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
In certain embodiments, the hydrochloride salt is a solid. In certain
embodiments, the hydrochloride salt is anhydrous. In certain embodiments,
the hydrochloride salt is nonhygroscopic. In certain embodiments, the
hydrochloride salt is amorphous. In certain embodiments, the
hydrochloride salt is crystalline. In certain embodiments, the
hydrochloride salt is in crystalline Form A.

[0223] The hydrochloride salt of the compound of Formula I and solid forms
thereof can be prepared according to the methods described in the
disclosure of U.S. Provisional Pat. App. No. 61/451,806. The
hydrochloride salt the solid forms thereof can be also prepared according
to other methods apparent to those of skill in the art.

[0224] The compound of Formula I provided herein contains one chiral
center, and can exist as a mixture of enantiomers, e.g., a racemic
mixture. This disclosure encompasses the use of stereomerically pure
forms of such a compound, as well as the use of mixtures of those forms.
For example, mixtures comprising equal or unequal amounts of the
enantiomers of the compound of Formula I provided herein may be used in
methods and compositions disclosed herein. These isomers may be
asymmetrically synthesized or resolved using standard techniques such as
chiral columns or chiral resolving agents. See, e.g., Jacques, J., et
al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New
York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.
L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and
Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268
(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, 1N, 1972).

[0225] It should be noted that if there is a discrepancy between a
depicted structure and a name given that structure, the depicted
structure is to be accorded more weight. In addition, if the
stereochemistry of a structure or a portion of a structure is not
indicated with, for example, bold or dashed lines, the structure or
portion of the structure is to be interpreted as encompassing all
stereoisomers of the structure.

5.4 SECOND ACTIVE AGENTS

[0226] A compound provided herein, e.g., the compound of Formula I, or an
enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof, can be combined with one or more other pharmacologically active
compounds ("second active agents") in methods and compositions provided
herein. It is believed that certain combinations work synergistically in
the treatment of particular types of cancer, and certain diseases and
conditions associated with or characterized by undesired angiogenesis.
The compound of Formula I provided herein can also work to alleviate
adverse effects associated with certain second active agents, and some
second active agents can be used to alleviate adverse effects associated
with the compound of Formula I provided herein.

[0227] One or more second active ingredients or agents can be used in the
methods and compositions provided herein with the compound of Formula I
provided herein. Second active agents can be large molecules (e.g.,
proteins) or small molecules (e.g., synthetic inorganic, organometallic,
or organic molecules).

[0228] Examples of large molecule active agents include, but are not
limited to, hematopoietic growth factors, cytokines, and monoclonal and
polyclonal antibodies. In certain embodiments, large molecule active
agents are biological molecules, such as naturally occurring or
artificially made proteins. Proteins that are particularly useful in this
disclosure include proteins that stimulate the survival and/or
proliferation of hematopoietic precursor cells and immunologically active
poietic cells in vitro or in vivo. Others stimulate the division and
differentiation of committed erythroid progenitors in cells in vitro or
in vivo. Particular proteins include, but are not limited to:
interleukins, such as IL-2 (including recombinant IL-II ("rIL2") and
canarypox IL-2), IL-10, IL-12, and IL-18; interferons, such as interferon
alfa-2a, interferon alfa-2b, interferon alfa-n1, interferon alfa-n3,
interferon beta-I a, and interferon gamma-I b; GM-CF and GM-CSF; and EPO.

[0229] Particular proteins that can be used in the methods and
compositions of the disclosure include, but are not limited to:
filgrastim, which is sold in the United States under the trade name
NEUPOGEN® (Amgen, Thousand Oaks, Calif.); sargramostim, which is sold
in the United States under the trade name LEUKINE® (Immunex, Seattle,
Wash.); and recombinant EPO, which is sold in the United States under the
trade name EPGEN® (Amgen, Thousand Oaks, Calif.).

[0230] Inhibitors of ActRII receptors or activin-ActRII inhibitors may be
used in the methods and compositions provided herein. ActRII receptors
include ActRIIA inhibitors and ActRIIB inhibitors. Inhibitors of ActRII
receptors can be polypeptides comprising activin-binding domains of
ActRII. In certain embodiments, the activin-binding domain comprising
polypeptides are linked to an Fc portion of an antibody (i.e., a
conjugate comprising an activin-binding domain comprising polypeptide of
an ActRII receptor and an Fc portion of an antibody is generated). In
certain embodiments, the activin-binding domain is linked to an Fc
portion of an antibody via a linker, e.g., a peptide linker. Examples of
such non-antibody proteins selected for activin or ActRIIA binding and
methods for design and selection of the same are found in WO/2002/088171,
WO/2006/055689, WO/2002/032925, WO/2005/037989, US 2003/0133939, and US
2005/0238646, each of which is incorporated herein by reference in its
entirety.

[0231] Recombinant and mutated forms of GM-CSF can be prepared as
described in U.S. Pat. Nos. 5,391,485; 5,393,870; and 5,229,496; the
disclosure of each of which is incorporated herein by reference in its
entirety. Recombinant and mutated forms of G-CSF can be prepared as
described in U.S. Pat. Nos. 4,810,643; 4,999,291; 5,528,823; and
5,580,755; the disclosure of each of which is incorporated herein by
reference in its entirety.

[0232] This disclosure encompasses the use of native, naturally occurring,
and recombinant proteins. The disclosure further encompasses mutants and
derivatives (e.g., modified forms) of naturally occurring proteins that
exhibit, in vivo, at least some of the pharmacological activity of the
proteins upon which they are based. Examples of mutants include, but are
not limited to, proteins that have one or more amino acid residues that
differ from the corresponding residues in the naturally occurring forms
of the proteins. Also encompassed by the term "mutants" are proteins that
lack carbohydrate moieties normally present in their naturally occurring
forms (e.g., nonglycosylated forms). Examples of derivatives include, but
are not limited to, pegylated derivatives and fusion proteins, such as
proteins formed by fusing IgG1 or IgG3 to the protein or active portion
of the protein of interest. See, e.g., Penichet, M. L. and Morrison, S.
L., J. Immunol. Methods 248:91-101 (2001).

[0233] Antibodies that can be used in combination with the compound of
Formula I provided herein include monoclonal and polyclonal antibodies.
Examples of antibodies include, but are not limited to, trastuzumab
(HERCEPTIN), rituximab (RITUXAN®), bevacizumab (AVASTIN®),
pertuzumab (OMNITARG®), tositumomab (BEXXAR®), edrecolomab
(PANOREX®), panitumumab and G250. The compound of Formula I provided
herein can also be combined with or used in combination with
anti-TNF-α antibodies.

[0234] Large molecule active agents may be administered in the form of
anti-cancer vaccines. For example, vaccines that secrete, or cause the
secretion of, cytokines such as IL-2, SCF, CXC14 (platelet factor 4),
G-CSF, and GM-CSF can be used in the methods, pharmaceutical
compositions, and kits of the disclosure. See, e.g., Emens, L. A., et
al., Curr. Opinion Mol. Ther. 3(1):77-84 (2001).

[0235] Second active agents that are small molecules can also be used to
alleviate adverse effects associated with the administration of the
compound of Formula I provided herein. However, like some large
molecules, many are believed to be capable of providing a synergistic
effect when administered with (e.g., before, after or simultaneously) the
compound of Formula I. Examples of small molecule second active agents
include, but are not limited to, anti-cancer agents, antibiotics,
immunosuppressive agents, and steroids.

[0239] Provided herein are methods relating to the use of mRNAs or
proteins as biomarkers to ascertain the effectiveness of cancer therapy.
mRNA or protein levels can be used to determine whether a particular
agent is likely to be successful in the treatment of a specific type of
cancer, e.g., non-Hodgkin's lymphoma.

[0240] A biological marker or "biomarker" is a substance whose detection
indicates a particular biological state, such as, for example, the
presence of cancer. In some embodiments, biomarkers can either be
determined individually, or several biomarkers can be measured
simultaneously.

[0241] In some embodiments, a "biomarker" indicates a change in the level
of mRNA expression that may correlate with the risk or progression of a
disease, or with the susceptibility of the disease to a given treatment.
In some embodiments, the biomarker is a nucleic acid, such as a mRNA or
cDNA.

[0242] In additional embodiments, a "biomarker" indicates a change in the
level of polypeptide or protein expression that may correlate with the
risk, susceptibility to treatment, or progression of a disease. In some
embodiments, the biomarker can be a polypeptide or protein, or a fragment
thereof. The relative level of specific proteins can be determined by
methods known in the art. For example, antibody based methods, such as an
immunoblot, enzyme-linked immunosorbent assay (ELISA), or other methods
can be used.

5.6 METHODS OF TREATMENT AND PREVENTION

[0243] In one embodiment, provided herein is a method of treating and
preventing cancer, which comprises administering to a patient a compound
provided herein, e.g., the compound of Formula I, or an enantiomer or a
mixture of enantiomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

[0244] In another embodiment, provided herein is method of managing
cancer, which comprises administering to a patient a compound provided
herein, e.g., the compound of Formula I, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof. Provided herein are
methods of treating or managing lymphoma, particularly non-Hodgkin's
lymphoma. In some embodiments, provided herein are methods for the
treatment or management of non-Hodgkin's lymphoma (NHL), including but
not limited to, diffuse large B-cell lymphoma (DLBCL), using prognostic
factors.

[0245] Also provided herein are methods of treating patients who have been
previously treated for cancer but are non-responsive to standard
therapies, as well as those who have not previously been treated. The
invention also encompasses methods of treating patients regardless of
patient's age, although some diseases or disorders are more common in
certain age groups. The invention further encompasses methods of treating
patients who have undergone surgery in an attempt to treat the disease or
condition at issue, as well as those who have not. Because patients with
cancer have heterogeneous clinical manifestations and varying clinical
outcomes, the treatment given to a patient may vary, depending on his/her
prognosis. The skilled clinician will be able to readily determine
without undue experimentation specific secondary agents, types of
surgery, and types of non-drug based standard therapy that can be
effectively used to treat an individual patient with cancer.

[0247] In certain embodiments, the cancer is a blood borne tumor. In
certain embodiments, the blood borne tumor is metastatic. In certain
embodiments, the blood borne tumor is drug resistant. In certain
embodiments, the cancer is myeloma or lymphoma.

[0248] In certain embodiments, the cancer is a solid tumor. In certain
embodiments, the solid tumor is metastatic. In certain embodiments, the
solid tumor is drug-resistant. In certain embodiments, the solid tumor is
hepatocellular carcinoma, prostate cancer, ovarian cancer, or
glioblastoma.

[0249] In certain embodiments, a therapeutically or prophylactically
effective amount of the compound is from about 0.005 to about 1,000 mg
per day, from about 0.01 to about 500 mg per day, from about 0.01 to
about 250 mg per day, from about 0.01 to about 100 mg per day, from about
0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, from
about 1 to about 100 mg per day, from about 0.01 to about 50 mg per day,
from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per
day, from about 1 to about 50 mg per day, from about 0.02 to about 25 mg
per day, or from about 0.05 to about 10 mg per day.

[0250] In certain embodiment, a therapeutically or prophylactically
effective amount is from about 0.005 to about 1,000 mg per day, from
about 0.01 to about 500 mg per day, from about 0.01 to about 250 mg per
day, from about 0.01 to about 100 mg per day, from about 0.1 to about 100
mg per day, from about 0.5 to about 100 mg per day, from about 1 to about
100 mg per day, from about 0.01 to about 50 mg per day, from about 0.1 to
about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1
to about 50 mg per day, from about 0.02 to about 25 mg per day, or from
about 0.05 to about 10 mg every other day.

[0251] In certain embodiments, the therapeutically or prophylactically
effective amount is about 1, about 2, about 5, about 10, about 15, about
20, about 25, about 30, about 40, about 45, about 50, about 60, about 70,
about 80, about 90, about 100, or about 150 mg per day.

[0252] In one embodiment, the recommended daily dose range of the compound
of Formula I for the conditions described herein lie within the range of
from about 0.5 mg to about 50 mg per day, preferably given as a single
once-a-day dose, or in divided doses throughout a day. In some
embodiments, the dosage ranges from about 1 mg to about 50 mg per day. In
other embodiments, the dosage ranges from about 0.5 to about 5 mg per
day. Specific doses per day include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,
30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,
48, 49 or 50 mg per day.

[0253] In a specific embodiment, the recommended starting dosage may be
0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day. In another
embodiment, the recommended starting dosage may be 0.5, 1, 2, 3, 4, or 5
mg per day. The dose may be escalated to 15, 20, 25, 30, 35, 40, 45 and
50 mg/day. In a specific embodiment, the compound can be administered in
an amount of about 25 mg/day to patients with NHL (e.g., DLBCL). In a
particular embodiment, the compound can be administered in an amount of
about 10 mg/day to patients with NHL (e.g., DLBCL).

[0254] In certain embodiments, the therapeutically or prophylactically
effective amount is from about 0.001 to about 100 mg/kg/day, from about
0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day, from
about 0.01 to about 10 mg/kg/day, from about 0.01 to about 9 mg/kg/day,
0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, from
about 0.01 to about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day,
from about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3
mg/kg/day, from about 0.01 to about 2 mg/kg/day, or from about 0.01 to
about 1 mg/kg/day.

[0255] The administered dose can also be expressed in units other than
mg/kg/day. For example, doses for parenteral administration can be
expressed as mg/m2/day. One of ordinary skill in the art would
readily know how to convert doses from mg/kg/day to mg/m2/day to
given either the height or weight of a subject or both (see,
www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 1
mg/kg/day for a 65 kg human is approximately equal to 38 mg/m2/day.

[0256] In certain embodiments, the amount of the compound administered is
sufficient to provide a plasma concentration of the compound at steady
state, ranging from about 0.001 to about 500 μM, about 0.002 to about
200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM,
from about 1 to about 50 μM, about 0.02 to about 25 μM, from about
0.05 to about 20 μM, from about 0.1 to about 20 μM, from about 0.5
to about 20 μM, or from about 1 to about 20 μM.

[0257] In other embodiments, the amount of the compound administered is
sufficient to provide a plasma concentration of the compound at steady
state, ranging from about 5 to about 100 nM, about 5 to about 50 nM,
about 10 to about 100 nM, about 10 to about 50 nM or from about 50 to
about 100 nM.

[0258] As used herein, the term "plasma concentration at steady state" is
the concentration reached after a period of administration of a compound
provided herein, e.g., the compound of Formula I, or an enantiomer or a
mixture of enantiomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Once
steady state is reached, there are minor peaks and troughs on the time
dependent curve of the plasma concentration of the compound.

[0259] In certain embodiments, the amount of the compound administered is
sufficient to provide a maximum plasma concentration (peak concentration)
of the compound, ranging from about 0.001 to about 500 μM, about 0.002
to about 200 μM, about 0.005 to about 100 μM, about 0.01 to about
50 μM, from about 1 to about 50 μM, about 0.02 to about 25 μM,
from about 0.05 to about 20 μM, from about 0.1 to about 20 μM, from
about 0.5 to about 20 μM, or from about 1 to about 20 μM.

[0260] In certain embodiments, the amount of the compound administered is
sufficient to provide a minimum plasma concentration (trough
concentration) of the compound, ranging from about 0.001 to about 500
μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM,
about 0.01 to about 50 μM, from about 1 to about 50 μM, about 0.01
to about 25 μM, from about 0.01 to about 20 μM, from about 0.02 to
about 20 μM, from about 0.02 to about 20 μM, or from about 0.01 to
about 20 μM.

[0261] In certain embodiments, the amount of the compound administered is
sufficient to provide an area under the curve (AUC) of the compound,
ranging from about 100 to about 100,000 ng*hr/mL, from about 1,000 to
about 50,000 ng*hr/mL, from about 5,000 to about 25,000 ng*hr/mL, or from
about 5,000 to about 10,000 ng*hr/mL.

[0262] In certain embodiments, the patient to be treated with one of the
methods provided herein has not been treated with anticancer therapy
prior to the administration of the compound of Formula I. In certain
embodiments, the patient to be treated with one of the methods provided
herein has been treated with anticancer therapy prior to the
administration of the compound of Formula I. In certain embodiments, the
patient to be treated with one of the methods provided herein has
developed drug resistance to the anticancer therapy.

[0263] The methods provided herein encompass treating a patient regardless
of patient's age, although some diseases or disorders are more common in
certain age groups. Further provided herein is a method for treating a
patient who has undergone surgery in an attempt to treat the disease or
condition at issue, as well in one who has not. Because the subjects with
cancer have heterogeneous clinical manifestations and varying clinical
outcomes, the treatment given to a particular subject may vary, depending
on his/her prognosis. The skilled clinician will be able to readily
determine without undue experimentation, specific secondary agents, types
of surgery, and types of non-drug based standard therapy that can be
effectively used to treat an individual subject with cancer.

[0264] Depending on the disease to be treated and the subject's condition,
the compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, may be administered by oral,
parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV,
intracistemal injection or infusion, subcutaneous injection, or implant),
inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g.,
transdermal or local) routes of administration. The compound of Formula
I, or an enantiomer or a mixture of enantiomers thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof, may be formulated, alone or together, in
suitable dosage unit with pharmaceutically acceptable excipients,
carriers, adjuvants and vehicles, appropriate for each route of
administration.

[0265] In one embodiment, the compound of Formula I, or an enantiomer or a
mixture of enantiomers thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is
administered orally. In another embodiment, the compound of Formula I, or
an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof, is administered parenterally. In yet another embodiment, the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered
intravenously.

[0266] The compound of Formula I, or an enantiomer or a mixture of
enantiomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof, can be delivered as
a single dose such as, e.g., a single bolus injection, or oral tablets or
pills; or over time, such as, e.g., continuous infusion over time or
divided bolus doses over time. The compound can be administered
repeatedly if necessary, for example, until the patient experiences
stable disease or regression, or until the patient experiences disease
progression or unacceptable toxicity. For example, stable disease for
solid tumors generally means that the perpendicular diameter of
measurable lesions has not increased by 25% or more from the last
measurement. Response Evaluation Criteria in Solid Tumors (RECIST)
Guidelines, Journal of the National Cancer Institute 92(3): 205-216
(2000). Stable disease or lack thereof is determined by methods known in
the art such as evaluation of patient symptoms, physical examination,
visualization of the tumor that has been imaged using X-ray, CAT, PET, or
MRI scan and other commonly accepted evaluation modalities.

[0267] The compound of Formula I, or an enantiomer or a mixture of
enantiomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof, can be administered
once daily (QD), or divided into multiple daily doses such as twice daily
(BID), three times daily (TID), and four times daily (QID). In addition,
the administration can be continuous (i.e., daily for consecutive days or
every day), intermittent, e.g., in cycles (i.e., including days, weeks,
or months of rest without drug). As used herein, the term "daily" is
intended to mean that a therapeutic compound, such as the compound of
Formula I, is administered once or more than once each day, for example,
for a period of time. The term "continuous" is intended to mean that a
therapeutic compound, such as the compound of Formula I, is administered
daily for an uninterrupted period of at least 10 days to 52 weeks. The
term "intermittent" or "intermittently" as used herein is intended to
mean stopping and starting at either regular or irregular intervals. For
example, intermittent administration of the compound of Formula I is
administration for one to six days per week, administration in cycles
(e.g., daily administration for two to eight consecutive weeks, then a
rest period with no administration for up to one week), or administration
on alternate days. The term "cycling" as used herein is intended to mean
that a therapeutic compound, such as the compound of Formula I, is
administered daily or continuously but with a rest period.

[0268] In some embodiments, the frequency of administration is in the
range of about a daily dose to about a monthly dose. In certain
embodiments, administration is once a day, twice a day, three times a
day, four times a day, once every other day, twice a week, once every
week, once every two weeks, once every three weeks, or once every four
weeks. In one embodiment, the compound of Formula I, or an enantiomer or
a mixture of enantiomers thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is
administered once a day. In another embodiment, the compound of Formula
I, or an enantiomer or a mixture of enantiomers thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof, is administered twice a day. In yet
another embodiment, the compound of Formula I, or an enantiomer or a
mixture of enantiomers thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is
administered three times a day. In still another embodiment, the compound
of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof, is administered four times a day.

[0269] In certain embodiments, the compound of Formula I, or an enantiomer
or a mixture of enantiomers thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is
administered once per day from one day to six months, from one week to
three months, from one week to four weeks, from one week to three weeks,
or from one week to two weeks. In certain embodiments, the compound of
Formula I, or a pharmaceutically acceptable salt or solvate thereof, is
administered once per day for one week, two weeks, three weeks, or four
weeks. In one embodiment, the compound of Formula I, or an enantiomer or
a mixture of enantiomers thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is
administered once per day for one week. In another embodiment, the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered once per day
for two weeks. In yet another embodiment, the compound of Formula I, or
an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof, is administered once per day for three weeks. In still another
embodiment, the compound of Formula I, or an enantiomer or a mixture of
enantiomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof, is administered
once per day for four weeks.

[0270] 5.6.1 Combination Therapy with a Second Active Agent

[0271] The compound of Formula I, or an enantiomer or a mixture of
enantiomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof, can also be
combined or used in combination with other therapeutic agents useful in
the treatment and/or prevention of cancer described herein.

[0272] In one embodiment, provided herein is a method of treating,
preventing, or managing cancer, comprising administering to a patient
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or an
enantiomer or a mixture of enantiomers thereof; or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof; in combination with one or more second active agents, and
optionally in combination with radiation therapy, blood transfusions, or
surgery. Examples of second active agents are disclosed herein (see,
e.g., section 5.3).

[0273] As used herein, the term "in combination" includes the use of more
than one therapy (e.g., one or more prophylactic and/or therapeutic
agents). However, the use of the term "in combination" does not restrict
the order in which therapies (e.g., prophylactic and/or therapeutic
agents) are administered to a patient with a disease or disorder. A first
therapy (e.g., a prophylactic or therapeutic agent such as a compound
provided herein, a compound provided herein, e.g., the compound of
Formula I, or an enantiomer or a mixture of enantiomers thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof) can be administered prior to (e.g., 5
minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6
hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks,
3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before),
concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30
minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24
hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5
weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a
second therapy (e.g., a prophylactic or therapeutic agent) to the
subject. Triple therapy is also contemplated herein.

[0274] Administration of the compound of Formula I and one or more second
active agents to a patient can occur simultaneously or sequentially by
the same or different routes of administration. The suitability of a
particular route of administration employed for a particular active agent
will depend on the active agent itself (e.g., whether it can be
administered orally without decomposing prior to entering the blood
stream) and the cancer being treated.

[0275] The route of administration of the compound of Formula I is
independent of the route of administration of a second therapy. In one
embodiment, the compound of Formula I is administered orally. In another
embodiment, the compound of Formula I is administered intravenously.
Thus, in accordance with these embodiments, the compound of Formula I is
administered orally or intravenously, and the second therapy can be
administered orally, parenterally, intraperitoneally, intravenously,
intraarterially, transdermally, sublingually, intramuscularly, rectally,
transbuccally, intranasally, liposomally, via inhalation, vaginally,
intraoccularly, via local delivery by catheter or stent, subcutaneously,
intraadiposally, intraarticularly, intrathecally, or in a slow release
dosage form. In one embodiment, the compound of Formula I and a second
therapy are administered by the same mode of administration, orally or by
IV. In another embodiment, the compound of Formula I is administered by
one mode of administration, e.g., by IV, whereas the second agent (an
anticancer agent) is administered by another mode of administration,
e.g., orally.

[0276] In one embodiment, the second active agent is administered
intravenously or subcutaneously and once or twice daily in an amount of
from about 1 to about 1000 mg, from about 5 to about 500 mg, from about
10 to about 350 mg, or from about 50 to about 200 mg. The specific amount
of the second active agent will depend on the specific agent used, the
type of disease being treated or managed, the severity and stage of
disease, and the amount of the compound of Formula I provided herein and
any optional additional active agents concurrently administered to the
patient. In certain embodiments, the second active agent is oblimersen
(GENASENSE®), GM-CSF, G-CSF, SCF, EPO, taxotere, irinotecan,
dacarbazine, transretinoic acid, topotecan, pentoxifylline,
ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX-2 inhibitor,
IL2, IL8, IL18, IFN, Ara-C, vinorelbine, or a combination thereof.

[0277] In certain embodiments, GM-CSF, G-CSF, SCF or EPO is administered
subcutaneously during about five days in a four or six week cycle in an
amount ranging from about 1 to about 750 mg/m2/day, from about 25 to
about 500 mg/m2/day, from about 50 to about 250 mg/m2/day, or
from about 50 to about 200 mg/m2/day. In certain embodiments, GM-CSF
may be administered in an amount of from about 60 to about 500
mcg/m2 intravenously over 2 hours or from about 5 to about 12
mcg/m2/day subcutaneously. In certain embodiments, G-CSF may be
administered subcutaneously in an amount of about 1 mcg/kg/day initially
and can be adjusted depending on rise of total granulocyte counts. The
maintenance dose of G-CSF may be administered in an amount of about 300
(in smaller patients) or 480 mcg subcutaneously. In certain embodiments,
EPO may be administered subcutaneously in an amount of 10,000 Unit 3
times per week.

[0278] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered with
melphalan and dexamethasone to patients with amyloidosis. In certain
embodiments, a compound provided herein, e.g., the compound of Formula I,
or an enantiomer or a mixture of enantiomers thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof, and steroids can be administered to
patients with amyloidosis.

[0279] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered with
gemcitabine and cisplatinum to patients with locally advanced or
metastatic transitional cell bladder cancer.

[0282] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered with
temozolomide to patients with neuroendocrine tumors.

[0283] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered with
gemcitabine to patients with recurrent or metastatic head or neck cancer.

[0284] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered with
gemcitabine to patients with pancreatic cancer.

[0285] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered to patients
with colon cancer in combination with ARISA®, avastatin, taxol,
and/or taxotere.

[0286] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered with
capecitabine and/or PLX4032 (Plexxikon) to patients with refractory
colorectal cancer or patients who fail first line therapy or have poor
performance in colon or rectal adenocarcinoma.

[0287] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered in
combination with fluorouracil, leucovorin, and irinotecan to patients
with Dukes C & D colorectal cancer or to patients who have been
previously treated for metastatic colorectal cancer.

[0288] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered to patients
with refractory colorectal cancer in combination with capecitabine,
xeloda, and/or CPT-11.

[0289] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered with
capecitabine and irinotecan to patients with refractory colorectal cancer
or to patients with unresectable or metastatic colorectal carcinoma.

[0290] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered alone or in
combination with interferon alpha or capecitabine to patients with
unresectable or metastatic hepatocellular carcinoma; or with cisplatin
and thiotepa to patients with primary or metastatic liver cancer.

[0291] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered in
combination with pegylated interferon alpha to patients with Kaposi's
sarcoma.

[0292] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered in
combination with fludarabine, carboplatin, and/or topotecan to patients
with refractory or relapsed or high-risk acuted myelogenous leukemia.

[0293] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered in
combination with liposomal daunorubicin, topotecan and/or cytarabine to
patients with unfavorable karotype acute myeloblastic leukemia.

[0294] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered in
combination with gemcitabine, abraxane, erlotinib, geftinib, and/or
irinotecan to patients with non-small cell lung cancer.

[0295] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered in
combination with carboplatin and irinotecan to patients with non-small
cell lung cancer.

[0296] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered with
doxetaxol to patients with non-small cell lung cancer who have been
previously treated with carbo/VP 16 and radiotherapy.

[0297] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered in
combination with carboplatin and/or taxotere, or in combination with
carboplatin, pacilitaxel and/or thoracic radiotherapy to patients with
non-small cell lung cancer.

[0298] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered in
combination with taxotere to patients with stage IIIB or IV non-small
cell lung cancer.

[0299] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered in
combination with oblimersen (Genasense®) to patients with small cell
lung cancer.

[0300] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered in
combination with ABT-737 (Abbott Laboratories) and/or obatoclax
(GX15-070) to patients with lymphoma and other blood cancers.

[0301] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered alone or in
combination with a second active ingredient such as vinblastine or
fludarabine to patients with various types of lymphoma, including, but
not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous
T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma
or relapsed or refractory low grade follicular lymphoma.

[0302] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered in
combination with taxotere, IL-2, IFN, GM-CSF, PLX4032 (Plexxikon) and/or
dacarbazine to patients with various types or stages of melanoma.

[0303] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered alone or in
combination with vinorelbine to patients with malignant mesothelioma, or
stage IIIB non-small cell lung cancer with pleural implants or malignant
pleural effusion mesothelioma syndrome.

[0305] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered to patients
with relapsed or refractory multiple myeloma in combination with
doxorubicin (Doxil®), vincristine and/or dexamethasone
(Decadron®).

[0306] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered to patients
with various types or stages of ovarian cancer such as peritoneal
carcinoma, papillary serous carcinoma, refractory ovarian cancer or
recurrent ovarian cancer, in combination with taxol, carboplatin,
doxorubicin, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone,
or a combination thereof.

[0308] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered to patients
with various types or stages of renal cell cancer, in combination with
capecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrex®, or a
combination thereof.

[0309] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered to patients
with various types or stages of gynecologic, uterus or soft tissue
sarcoma cancer in combination with IFN, a COX-2 inhibitor such as
Celebrex®, and/or sulindac.

[0310] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered to patients
with various types or stages of solid tumors in combination with
celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN,
tamoxifen, IL-2, GM-CSF, or a combination thereof.

[0311] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, is administered to patients
with scleroderma or cutaneous vasculitis in combination with celebrex,
etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen,
IL-2, GM-CSF, or a combination thereof.

[0312] Also encompassed herein is a method of increasing the dosage of an
anti-cancer drug or agent that can be safely and effectively administered
to a patient, which comprises administering to the patient (e.g., a
human) or an enantiomer or a mixture of enantiomers thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof. Patients that can benefit by this method
are those likely to suffer from an adverse effect associated with
anti-cancer drugs for treating a specific cancer of the skin,
subcutaneous tissue, lymph nodes, brain, lung, liver, bone, intestine,
colon, heart, pancreas, adrenal, kidney, prostate, breast, colorectal, or
combinations thereof. The administration of a compound provided herein,
e.g., the compound of Formula I, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof, alleviates or
reduces adverse effects which are of such severity that it would
otherwise limit the amount of anti-cancer drug.

[0313] In one embodiment, a compound provided herein, e.g., the compound
of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof, is administered orally and daily in an
amount ranging from about 0.1 to about 150 mg, from about 1 to about 50
mg, or from about 2 to about 25 mg, prior to, during, or after the
occurrence of the adverse effect associated with the administration of an
anti-cancer drug to a patient. In certain embodiments, a compound
provided herein, e.g., the compound of Formula I, or an enantiomer or a
mixture of enantiomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is
administered in combination with specific agents such as heparin,
aspirin, coumadin, or G-CSF to avoid adverse effects that are associated
with anti-cancer drugs such as but not limited to neutropenia or
thrombocytopenia.

[0314] In one embodiment, a compound provided herein, e.g., the compound
of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof, is administered to patients with
diseases and disorders associated with or characterized by, undesired
angiogenesis in combination with additional active ingredients,
including, but not limited to, anti-cancer drugs, anti-inflammatories,
antihistamines, antibiotics, and steroids.

[0315] In another embodiment, encompassed herein is a method of treating,
preventing and/or managing cancer, which comprises administering the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, in conjunction with (e.g.
before, during, or after) conventional therapy including, but not limited
to, surgery, immunotherapy, biological therapy, radiation therapy, or
other non-drug based therapy presently used to treat, prevent or manage
cancer. The combined use of the compound provided herein and conventional
therapy may provide a unique treatment regimen that is unexpectedly
effective in certain patients. Without being limited by theory, it is
believed that the compound of Formula I may provide additive or
synergistic effects when given concurrently with conventional therapy.

[0316] As discussed elsewhere herein, encompassed herein is a method of
reducing, treating and/or preventing adverse or undesired effects
associated with conventional therapy including, but not limited to,
surgery, chemotherapy, radiation therapy, hormonal therapy, biological
therapy and immunotherapy. A compound provided herein, e.g., the compound
of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof, and other active ingredient can be
administered to a patient prior to, during, or after the occurrence of
the adverse effect associated with conventional therapy.

[0317] In one embodiment, the compound of Formula I can be administered in
an amount ranging from about 0.1 to about 150 mg, from about 1 to about
25 mg, or from about 2 to about 10 mg orally and daily alone, or in
combination with a second active agent disclosed herein (see, e.g.,
section 4.3), prior to, during, or after the use of conventional therapy.

[0318] In certain embodiments, a compound provided herein, e.g., the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, and doxetaxol are
administered to patients with non-small cell lung cancer who were
previously treated with carbo/VP 16 and radiotherapy.

[0319] 5.6.2 Use with Transplantation Therapy

[0320] The compound of Formula I provided herein can be used to reduce the
risk of Graft Versus Host Disease (GVHD). Therefore, encompassed herein
is a method of treating, preventing and/or managing cancer, which
comprises administering the compound of Formula I, or an enantiomer or a
mixture of enantiomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in
conjunction with transplantation therapy.

[0321] As those of ordinary skill in the art are aware, the treatment of
cancer is often based on the stages and mechanism of the disease. For
example, as inevitable leukemic transformation develops in certain stages
of cancer, transplantation of peripheral blood stem cells, hematopoietic
stem cell preparation or bone marrow may be necessary. The combined use
of the compound of Formula I provided herein and transplantation therapy
provides a unique and unexpected synergism. In particular, the compound
of Formula I exhibits immunomodulatory activity that may provide additive
or synergistic effects when given concurrently with transplantation
therapy in patients with cancer.

[0322] The compound of Formula I can work in combination with
transplantation therapy reducing complications associated with the
invasive procedure of transplantation and risk of GVHD. Encompassed
herein is a method of treating, preventing and/or managing cancer which
comprises administering to a patient (e.g., a human) the compound of
Formula I, or an enantiomer or a mixture of enantiomers thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof, before, during, or after the
transplantation of umbilical cord blood, placental blood, peripheral
blood stem cell, hematopoietic stem cell preparation, or bone marrow.
Some examples of stem cells suitable for use in the methods provided
herein are disclosed in U.S. Pat. No. 7,498,171, the disclosure of which
is incorporated herein by reference in its entirety.

[0323] In one embodiment, the compound of Formula I is administered to
patients with multiple myeloma before, during, or after the
transplantation of autologous peripheral blood progenitor cell.

[0324] In another embodiment, the compound of Formula I is administered to
patients with relapsing multiple myeloma after the stem cell
transplantation.

[0325] In yet another embodiment, the compound of Formula I and prednisone
are administered as maintenance therapy to patients with multiple myeloma
following the transplantation of autologous stem cell.

[0326] In yet another embodiment, the compound of Formula I and
dexamethasone are administered as salvage therapy for low risk post
transplantation to patients with multiple myeloma.

[0327] In yet another embodiment, the compound of Formula I and
dexamethasone are administered as maintenance therapy to patients with
multiple myeloma following the transplantation of autologous bone marrow.

[0328] In yet another embodiment, the compound of Formula I is
administered following the administration of high dose of melphalan and
the transplantation of autologous stem cell to patients with chemotherapy
responsive multiple myeloma.

[0329] In yet another embodiment, the compound of Formula I and PEG
INTRO-A are administered as maintenance therapy to patients with multiple
myeloma following the transplantation of autologous CD34-selected
peripheral stem cell.

[0330] In yet another embodiment, the compound of Formula I is
administered with post transplant consolidation chemotherapy to patients
with newly diagnosed multiple myeloma to evaluate anti-angiogenesis.

[0331] In still another embodiment, the compound of Formula I and
dexamethasone are administered as maintenance therapy after DCEP
consolidation, following the treatment with high dose of melphalan and
the transplantation of peripheral blood stem cell to 65 years of age or
older patients with multiple myeloma.

[0332] In one embodiment, the compound of Formula I is administered to
patients with NHL (e.g., DLBCL) before, during, or after the
transplantation of autologous peripheral blood progenitor cell.

[0333] In another embodiment, the compound of Formula I is administered to
patients with NHL (e.g., DLBCL) after a stem cell transplantation.

[0334] 5.6.3 Cycling Therapy

[0335] In certain embodiments, the prophylactic or therapeutic agents
provided herein are cyclically administered to a patient. Cycling therapy
involves the administration of an active agent for a period of time,
followed by a rest for a period of time, and repeating this sequential
administration. Cycling therapy can reduce the development of resistance
to one or more of the therapies, avoid, or reduce the side effects of one
of the therapies, and/or improves the efficacy of the treatment.

[0336] Consequently, in certain embodiments, the compound of Formula I
provided herein is administered daily in a single or divided doses in a
four to six week cycle with a rest period of about a week or two weeks.
The cycling method further allows the frequency, number, and length of
dosing cycles to be increased. Thus, encompassed herein in certain
embodiments is the administration of a compound provided herein, e.g.,
the compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, for more cycles than are
typical when it is administered alone. In certain embodiments, a compound
provided herein, e.g., the compound of Formula I, or an enantiomer or a
mixture of enantiomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is
administered for a greater number of cycles that would typically cause
dose-limiting toxicity in a patient to whom a second active ingredient is
not also being administered.

[0337] In one embodiment, the compound of Formula I is administered daily
and continuously for three or four weeks at a dose of from about 0.1 to
about 150 mg/d followed by a break of one or two weeks.

[0338] In another embodiment, the compound of Formula I and a second
active ingredient are administered orally, with administration of the
compound of Formula I occurring 30 to 60 minutes prior to a second active
ingredient, during a cycle of four to six weeks. In certain embodiments,
the combination of the compound of Formula I and a second active
ingredient is administered by intravenous infusion over about 90 minutes
every cycle. In certain embodiments, one cycle comprises the
administration from about 0.1 to about 150 mg/day of the compound of
Formula I and from about 50 to about 200 mg/m2/day of a second
active ingredient daily for three to four weeks and then one or two weeks
of rest. In certain embodiments, the number of cycles during which the
combinatorial treatment is administered to a patient is ranging from
about one to about 24 cycles, from about two to about 16 cycles, or from
about four to about three cycles.

5.7 PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS

[0339] In one embodiment, provided herein are pharmaceutical compositions
and dosage forms, which comprise the compound of Formula I, or an
enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
thereof. In another embodiment, pharmaceutical compositions and dosage
forms further comprise one or more excipients.

[0340] In certain embodiments, pharmaceutical compositions and dosage
forms provided herein also comprise one or more additional active
ingredients. Consequently, pharmaceutical compositions and dosage forms
provided herein comprise the compound of Formula I, or an enantiomer or a
mixture of enantiomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and a
second active agent. Examples of optional second, or additional, active
ingredients are disclosed herein (see, e.g., section 4.3).

[0342] The composition, shape, and type of dosage forms provided herein
may vary depending on their use. For example, a dosage form used in the
acute treatment of a disease may contain larger amounts of one or more of
the active ingredients than a dosage form used in the chronic treatment
of the same disease. Similarly, a parenteral dosage form may contain
smaller amounts of one or more of the active ingredients than an oral
dosage form used to treat the same disease. See, e.g., Remington's
Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

[0343] Whether a particular excipient is suitable for incorporation into a
pharmaceutical composition or dosage form provided herein depends on a
variety of factors, including, but not limited to, the route of
administration. For example, oral dosage forms such as tablets may
contain excipients not suited for use in parenteral dosage forms. The
suitability of a particular excipient may also depend on the specific
active ingredients in the dosage form. For example, the decomposition of
some active ingredients may be accelerated by some excipients such as
lactose, or when exposed to water. Active ingredients that comprise
primary or secondary amines are particularly susceptible to such
accelerated decomposition. Consequently, encompassed herein are
pharmaceutical compositions and dosage forms that contain little, if any,
lactose. As used herein, the term "lactose-free" means that the amount of
lactose present, if any, is insufficient to substantially increase the
degradation rate of an active ingredient.

[0345] Further encompassed herein are anhydrous pharmaceutical
compositions and dosage forms comprising active ingredients, since water
can facilitate the degradation of some compounds. For example, the
addition of water (e.g., 5%) is widely accepted in the pharmaceutical
arts as a means of simulating long-term storage in order to determine
characteristics such as shelf-life or the stability of formulations over
time. See, e.g., Jens T. Carstensen, Drug Stability: Principles &
Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect,
water and heat accelerate the decomposition of some compounds. Thus, the
effect of water on a formulation can be of great significance since
moisture and/or humidity are commonly encountered during manufacture,
handling, packaging, storage, shipment, and use of formulations.

[0346] Anhydrous pharmaceutical compositions and dosage forms provided
herein can be prepared using anhydrous or low moisture containing
ingredients and low moisture or low humidity conditions. Pharmaceutical
compositions and dosage forms that comprise lactose and at least one
active ingredient that comprises a primary or secondary amine are
preferably anhydrous if substantial contact with moisture and/or humidity
during manufacturing, packaging, and/or storage is expected.

[0347] An anhydrous pharmaceutical composition should be prepared and
stored such that its anhydrous nature is maintained. Accordingly, in
certain embodiments, provided herein are anhydrous compositions packaged
using materials to prevent exposure to water such that they can be
included in suitable formulary kits. Examples of suitable packaging
include, but are not limited to, hermetically sealed foils, plastics,
unit dose containers (e.g., vials), blister packs, and strip packs.

[0348] Encompassed herein are pharmaceutical compositions and dosage forms
that comprise one or more compounds that reduce the rate by which an
active ingredient will decompose. Such compounds, which are referred to
herein as "stabilizers," include, but are not limited to, antioxidants
such as ascorbic acid, pH buffers, or salt buffers.

[0349] Like the amounts and types of excipients, the amounts and specific
types of active ingredients in a dosage form may differ depending on
factors such as, but not limited to, the route by which it is to be
administered to patients. In certain embodiments, the dosage forms
provided herein comprise the compound of Formula I, or an enantiomer or a
mixture of enantiomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in an
amount ranging from about 0.10 to about 1000 mg, from about 0.10 to about
500 mg, from about 0.10 to about 200 mg, from about 0.10 to about 150 mg,
from about 0.10 to about 100 mg, or from about 0.10 to about 50 mg. In
certain embodiments, the dosage forms provided herein comprise the
compound of Formula I, or an enantiomer or a mixture of enantiomers
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
co-crystal, clathrate, or polymorph thereof, in an amount of about 0.1,
about 1, about 2, about 5, about 7.5, about 10, about 12.5, about 15,
about 17.5, about 20, about 25, about 50, about 100, about 150, or about
200 mg.

[0350] 5.7.1 Oral Dosage Forms

[0351] In certain embodiments, pharmaceutical compositions provided herein
that are suitable for oral administration are formulated as discrete
dosage forms, examples of which include, but are not limited to, tablets
(e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored
syrups). Such dosage forms contain predetermined amounts of active
ingredients and may be prepared by some known methods of pharmacy. See
generally, Remington's Pharmaceutical Sciences, 18th ed., Mack
Publishing, Easton Pa. (1990).

[0352] In certain embodiments, the oral dosage forms provided herein are
prepared by combining the active ingredients in an intimate admixture
with at least one excipient according to conventional pharmaceutical
compounding techniques. Excipients can take a wide variety of forms
depending on the form of preparation desired for administration. For
example, excipients suitable for use in oral liquid or aerosol dosage
forms include, but are not limited to, water, glycols, oils, alcohols,
flavoring agents, preservatives, and coloring agents. Examples of
excipients suitable for use in solid oral dosage forms (e.g., powders,
tablets, capsules, and caplets) include, but are not limited to,
starches, sugars, micro-crystalline cellulose, diluents, granulating
agents, lubricants, binders, and disintegrating agents.

[0353] Because of their ease of administration, tablets and capsules
represent the most advantageous oral dosage unit forms, in which case
solid excipients are employed. If desired, tablets can be coated by
standard aqueous or nonaqueous techniques. Such dosage forms may be
prepared by some known methods of pharmacy. In certain embodiments,
pharmaceutical compositions and dosage forms are prepared by uniformly
and intimately admixing the active ingredients with liquid carriers,
finely divided solid carriers, or both, and then shaping the product into
the desired presentation if necessary.

[0354] In certain embodiments, a tablet is prepared by compression or
molding. In certain embodiments, compressed tablets are be prepared by
compressing in a suitable machine the active ingredients in a
free-flowing form, e.g., powder or granules, optionally mixed with an
excipient. In certain embodiments, molded tablets are made by molding in
a suitable machine a mixture of a powdered compound moistened with an
inert liquid diluent.

[0357] Examples of fillers suitable for use in the pharmaceutical
compositions and dosage forms provided herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and
mixtures thereof. In certain embodiments, the binder or filler in
pharmaceutical compositions provided herein is present in from about 50
to about 99 weight percent of the pharmaceutical composition or dosage
form.

[0358] Disintegrants are used in the compositions provided herein to
provide tablets the ability to disintegrate when exposed to an aqueous
environment. Tablets that contain too much disintegrant may disintegrate
in storage, while those that contain too little may not disintegrate at a
desired rate or under the desired conditions. Thus, a sufficient amount
of disintegrant that is neither too much nor too little to detrimentally
alter the release of the active ingredients should be used to form solid
oral dosage forms provided herein. The amount of disintegrant used varies
based upon the type of formulation. In certain embodiments, the
pharmaceutical compositions provided herein comprise from about 0.5 to
about 15 weight percent or from about 1 to about 5 weight percent of
disintegrant.

[0361] In certain embodiments, provided herein is a solid oral dosage
form, comprising the compound of Formula I, or an enantiomer or a mixture
of enantiomers thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof; and one or more
excipients selected from anhydrous lactose, microcrystalline cellulose,
polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and
gelatin.

[0363] In certain embodiments, provided herein is a solid oral dosage
form, comprising a hydrochloride sale of the compound of Formula I, or an
enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
solvate, hydrate, co-crystal, clathrate, or polymorph thereof; and one or
more excipients selected from anhydrous lactose, microcrystalline
cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous
silica, and gelatin.

[0364] In certain embodiments, provided herein is a solid oral dosage
form, comprising a hydrochloride sale of the compound of Formula I, or an
enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
solvate, hydrate, co-crystal, clathrate, or polymorph thereof; and
anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone,
stearic acid, colloidal anhydrous silica, and gelatin.

[0365] 5.7.2 Delayed Release Dosage Forms

[0366] In certain embodiments, the active ingredients provided herein are
administered by controlled release means or by delivery devices. Examples
include, but are not limited to, those described in U.S. Pat. Nos.
3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719, 5,674,533,
5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and
5,733,566, each of which is incorporated herein by reference in its
entirety. In certain embodiments, such dosage forms are be used to
provide slow or controlled-release of one or more active ingredients
using, for example, hydropropylmethyl cellulose, other polymer matrices,
gels, permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, microspheres, or a combination thereof to
provide the desired release profile in varying proportions. Encompassed
herein are single unit dosage forms suitable for oral administration,
including, but not limited to, tablets, capsules, gelcaps, and caplets
that are adapted for controlled-release.

[0367] All controlled-release pharmaceutical products have a common goal
of improving drug therapy over that achieved by their non-controlled
counterparts. Ideally, the use of an optimally designed
controlled-release preparation in medical treatment is characterized by a
minimum of drug substance being employed to cure or control the condition
in a minimum amount of time. Advantages of controlled-release
formulations include extended activity of the drug, reduced dosage
frequency, and increased patient compliance. In addition,
controlled-release formulations can be used to affect the time of onset
of action or other characteristics, such as blood levels of the drug, and
can thus affect the occurrence of side (e.g., adverse) effects.

[0368] Most controlled-release formulations are designed to initially
release an amount of drug (active ingredient) that promptly produces the
desired therapeutic effect, and gradually and continually release of
other amounts of drug to maintain this level of therapeutic or
prophylactic effect over an extended period of time. In order to maintain
this constant level of drug in the body, the drug must be released from
the dosage form at a rate that will replace the amount of drug being
metabolized and excreted from the body. Controlled-release of an active
ingredient can be stimulated by various conditions including, but not
limited to, pH, temperature, enzymes, water, or other physiological
conditions or compounds.

[0369] 5.7.3 Parenteral Dosage Forms

[0370] Parenteral dosage forms can be administered to patients by various
routes including, but not limited to, subcutaneous, intravenous
(including bolus injection), intramuscular, and intraarterial. Because
their administration typically bypasses patients' natural defenses
against contaminants, parenteral dosage forms are preferably sterile or
capable of being sterilized prior to administration to a patient.
Examples of parenteral dosage forms include, but are not limited to,
solutions ready for injection, dry products ready to be dissolved or
suspended in a pharmaceutically acceptable vehicle for injection,
suspensions ready for injection, and emulsions.

[0372] Compounds that increase the solubility of one or more of the active
ingredients disclosed herein can also be incorporated into the parenteral
dosage forms provided herein. For example, cyclodextrin and its
derivatives can be used to increase the solubility of a compound provided
herein, e.g., the compound of Formula I, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof. See, e.g., U.S.
Pat. No. 5,134,127, the disclosure of which is incorporated herein by
reference in its entirety.

[0375] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide topical and mucosal dosage forms
encompassed herein depend on the particular tissue to which a given
pharmaceutical composition or dosage form will be applied. With that fact
in mind, in certain embodiments, the excipients include, but are not
limited to, water, acetone, ethanol, ethylene glycol, propylene glycol,
butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,
and mixtures thereof to form solutions, emulsions or gels, which are
non-toxic and pharmaceutically acceptable. Moisturizers or humectants can
also be added to pharmaceutical compositions and dosage forms if desired.
Additional examples of such ingredients can be found, e.g., in
Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack
Publishing, Easton Pa. (1980 & 1990).

[0376] The pH of a pharmaceutical composition or dosage form may also be
adjusted to improve delivery of one or more active ingredients.
Similarly, the polarity of a solvent carrier, its ionic strength, or
tonicity can be adjusted to improve delivery. Compounds such as stearates
can also be added to pharmaceutical compositions or dosage forms to
advantageously alter the hydrophilicity or lipophilicity of one or more
active ingredients so as to improve delivery. In this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying agent
or surfactant, and as a delivery-enhancing or penetration-enhancing
agent. Different salts, hydrates or solvates of the active ingredients
can be used to further adjust the properties of the resulting
composition.

[0377] 5.7.5 Kits

[0378] In certain embodiments, active ingredients provided herein are not
administered to a patient at the same time or by the same route of
administration. Therefore, encompassed herein are kits which, when used
by the medical practitioner, can simplify the administration of
appropriate amounts of active ingredients to a patient.

[0380] In certain embodiments, the kit provided herein further comprises a
device that is used to administer the active ingredients. Examples of
such devices include, but are not limited to, syringes, drip bags,
patches, and inhalers.

[0381] In certain embodiments, the kit provided herein further comprises
cells or blood for transplantation as well as pharmaceutically acceptable
vehicles that can be used to administer one or more active ingredients.
For example, if an active ingredient is provided in a solid form that
must be reconstituted for parenteral administration, the kit can comprise
a sealed container of a suitable vehicle in which the active ingredient
can be dissolved to form a particulate-free sterile solution that is
suitable for parenteral administration. Examples of pharmaceutically
acceptable vehicles include, but are not limited to: Water for Injection
USP; aqueous vehicles such as, but not limited to, Sodium Chloride
Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium
Chloride Injection, and Lactated Ringer's Injection; water-miscible
vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol,
and polypropylene glycol; and non-aqueous vehicles such as, but not
limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl
oleate, isopropyl myristate, and benzyl benzoate.

6. EXAMPLES

[0382] Certain embodiments of the invention are illustrated by the
following non-limiting examples.

[0387] Step 4: Two vials each with a suspension of
5-nitro-2-methyl-benzo[d][1,3]oxazin-4-one (0.60 g, 2.91 mmol) and
3-amino-piperidine-2,6-dione hydrogen chloride (0.48 g, 2.91 mmol) in
pyridine (15 mL) were heated at 170° C. for 10 minutes in a
microwave oven. The suspension was filtered and washed with pyridine (5
mL). The filtrate was concentrated in vacuo. The resulting mixture was
stirred in HCl (30 mL, 1N), ethyl acetate (15 mL) and ether (15 mL) for 2
hrs. The suspension was filtered and washed with water (30 mL) and ethyl
acetate (30 mL) to give a dark brown solid, which was stirred with
methanol (50 mL) at room temperature overnight. The suspension was
filtered and washed with methanol to give
3-(2-methyl-5-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a
black solid (490 mg, 27% yield). The solid was used in the next step
without further purification.

[0391] The PBMCs (2×105 cells) were plated in 96-well
flat-bottom Costar tissue culture plates (Corning, N.Y., USA) in
triplicate. The cells were stimulated with LPS (from Salmonella abortus
equi, Sigma cat. no. L-1887, St. Louis, Mo., USA) at 1 ng/mL final in the
absence or presence of compounds to be tested. The compounds were
dissolved in DMSO (Sigma) and further dilutions were done in culture
medium immediately before use. The final DMSO concentration in all assays
was about 0.25%. The compounds were added to cells 1 hour before LPS
stimulation. The cells were then incubated for 18-20 hours at 37°
C. in 5% CO2, and supernatants were then collected, diluted with
culture medium and assayed for TNFα levels by ELISA (Endogen,
Boston, Mass., USA). IC50 values were calculated using non-linear
regression, sigmoidal dose-response, constraining the top to 100% and
bottom to 0%, allowing variable slope (GraphPad Prism v3.02).

[0392] 6.2.2 Inhibition of MM Cell Proliferation

[0393] The ability of compounds to effect the proliferation of MM cell
lines was investigated in an in vitro study. Uptake of
[3H]-thymidine by H929 MM cells and 7-AAD uptake in several MM cell
lines (H929, U266B1, Anb1-6, KMS-34, OPM-2, DF-15, DF15/R, CAG, MM1.S and
LP-1) was measured as an indicator of cell proliferation. Cells were
incubated in the presence of compounds for 72 hours ([3H]-thymidine
was included for the last 6 hours of the incubation period) or 5 days
followed by 7-AAD uptake to measure and count viable cells.

6.2.3 Cytokine Production by T Cells

[0394] T cells were isolated from buffy coat by negative selection using
the RosetteSep® T Cell Enrichment Cocktail. The manufacturer's
procedures were followed accordingly. All 96-well plates were pre-coated
with 3 μg/ml anti-human CD3 antibody in 100 μl 1×PBS for 4
hours at 37° C. The plates were washed three times with RPMI-1640
Complete Media prior to the T cell assay. T cells were then plated in CD3
pre-coated plates at a density of 2.5×105 cells/well in 180
μl RPMI-1640 Complete Media. The cells were treated with 20 μl
10× titrated compounds at 10, 1, 0.1, 0.01, 0.001, 0.0001 and
0.00001 μM. Final DMSO concentrations were 0.25%. The plates were
incubated for 48 hours at 37° C., 5% CO2. After 48 hours, the
supernatants were harvested and tested by a multi-plex cytomteric bead
array (CBA) assay for the following cytokines/chemokines: IL-2, IL-3,
IL-5, IL-10, IL-13, IL-15, IL-17a, GM-CSF, G-SCF, IFN-γ,
TNF-α and RANTES. The CBA plates were analyzed on the Luminex IS100
instrument.

[0395] Cytokine levels were normalized to the amount produced in the
presence of the amount of a compound tested, and EC50 values were
calculated using non-linear regression, sigmoidal dose-response,
constraining the top to 100% and bottom to 0%, allowing variable slope
(GraphPad Prism v3.02).

[0396] Anti-CD3-Stimulated Human T Cell Assay

[0397] All 96-well plates were pre-coated with 3 μg/mL anti-human CD3
antibody in 100 μL 1×PBS for 4 hours at 37° C. The plates
were washed 3 times with RPMI-1640 Complete Media prior to the T cell
assay. The T cells were then plated in anti-CD3-pre-coated plates at a
density of 2.5×105 cells/well in 180 μL RPMI-1640 Complete
Media. The cells were treated with 20 μL 10× titrated Celgene
compounds at 10, 1, 0.1, 0.01, 0.001, 0.0001, and 0.00001 μM in
duplicate. The final DMSO concentrations were 0.25%. The plates were
incubated for 48 hours at 37° C., 5% CO2. After 48 hours, the
supernatants were harvested and tested by a multiplex cytometric bead
array (CBA) assay for the following cytokines/chemokines: IL-2, IL-3,
IL-5, IL-10, IL-13, IL-15, IL-17A, GM-CSF, G-CSF, IFN-γ,
TNF-α, and RANTES. The CBA plates were analyzed on the Luminex
IS100 instrument.

[0398] 6.2.4 Cytotoxicity Assay

[0399] Cells line Farage, DOHH2 and Rec-1 were obtained from American Type
Culture Collection (Manassas, Va., USA) Cytotoxicity assays were measured
in 3 day ATP production assays as follows:

[0400] The cells were plated in black/clear-bottom 96-well TC plates (BD
Falcon, Cat #353948) at 3000 cells/75 μL (for DoHH-2 and Farage cells)
or 6000 cells/75 μL (Rec-1 cells) media per well. Stock solutions
(40×) of compounds were prepared in DMSO and 4× solutions
were prepared by diluting the 40× stock solutions 1:10 with 1% DMSO
in culture medium In each assay plate well, 25 μL of the compound of
Formula I in 1% DMSO were added to the cells in triplicate so that the
final volume was 100 μL and [DMSO] final was 0.25%. Plates were then
sealed with breathable sealing films (ISC BioExpress, Cat # T-2421-50)
and placed in a 37° C., 5% CO2 humidified incubator for 72
hours. In addition, cells were seeded in a separate plate in the same
manner as above, 25 μL medium in 1% DMSO was added to each well. This
plate was immediately tested in the CellTiter-Glo Luminescent Cell
Viability Assay (Promega, Cat # G7572) as 0 time point and the results
were used to calculate GIC50 in the Farage and DOHH-2 cell
experiments

[0401] After 72 hours of incubation, 100 μL of CellTiter-Glo reagent
were added to each well and incubated at room temperature with gentle
shaking for 30 minutes. The plates were then analyzed for luminescence in
a TopCount NXT Reader (Packard). Each well was counted for one second.
Values for duplicate wells were averaged and then compared to the zero
time point DMSO control (0% inhibition) to calculate the percentage
inhibition of cell growth. Mean DOHH-2 GIC50 values and Farage
GIC50 values were calculated from three experiments. Rec-1 IC50
values were calculated from two experiments.

[0402] 6.2.5 Cell Cycle Analysis

[0403] Cells were treated with DMSO or an amount of a compound provided
herein for 48 hours. Propidium iodide staining for cell cycle was
performed using CycleTEST PLUS (Becton Dickinson) according to
manufacturer's protocol. Following staining, cells were analyzed by a
FACSCalibur flow cytometer using ModFit LT software (Becton Dickinson).

[0404] 6.2.6 Apoptosis Analysis

[0405] Cells were treated with DMSO or an amount of a compound provided
herein at various time points, then washed with annexin-V wash buffer (BD
Biosciences). Cells were incubated with annexin-V binding protein and
propidium iodide (BD Biosciences) for 10 minutes. Samples were analyzed
using flow cytometry.

[0406] 6.2.7 NK Cell Analysis

[0407] Ninety-six-well flat-bottom plates were coated with 100 μg/mL of
human IgG (Sigma) overnight at 4° C. The next day, unbound IgG was
washed away with cold 1×PBS. NK cells were then plated in the
IgG-coated 96-well plates at 2×105 cells per well in 180 μL
RPMI-1640 Media and 10 ng/mL of rhIL-2 (R & D Systems, MN) was added.
Test compounds were added in a volume of 20 μL DMSO. Final
concentrations of test compounds were 0.0001, 0.001, 0.01, 0.1, 1, or 10
μM. Final DMSO concentrations were 0.25%. After 48 hours, the
supernatants were harvested and analyzed by ELISA for IFN-γ
production.

[0408] 6.2.8 Results

[0409] The biological activities of the compound of Formula I are
summarized in Tables 1 to 5. In the anti-CD3-stimulated human T cell
assay described above, the compound of Formula I enhanced production of
IL-2, IL-3, IL-5, IL-10, IL-15, GM-CSF, INF-γ, RANTES, and
TNF-α at concentrations of 0.01 to 10 μM. Enhancement of IL-2,
IL-3, IL-13, GM-CSF, TNF-α, and RANTES by the compound was
concentration-dependent. At a concentration of 0.1 μM of the compound
of Formula I, production of IL-2 and IL-13 was enhanced to levels
14× and 7× those in control cells, respectively. At a
concentration of 1 μM of the compound of Formula I, production of IL-2
and IL-13 was enhanced to levels 17× and 8× those in control
cells, respectively. The compound enhanced IL-10 production 2-fold at low
concentrations (≦0.01 μM) but inhibited IL-10 production at 1
and 10 μM. The compound increased IL-5 production 3- and 4-fold at
0.01 and 0.1 μM, respectively, showing less enhancement at both lower
and higher concentrations.

[0410] Additionally, it was observed that, in a human umbilical artery
assay, the compound of Formula I was a potent anti-angiogenic agent with
an IC50 of 9.4 nM; and the compound of Formula I did not inhibit
HUVEC proliferation.

[0411] In a mouse Matrigel® angiogenesis assay, it was observed that
the compound of Formula I significantly inhibited blood vessel growth at
30 mpk and exhibited a dose dependent inhibition of angiogenesis.

[0412] It was observed that the compound of Formula I induced G1 arrest in
DoHH2 and WSU-DLCL2. It was also observed that, in proliferation assays,
the compound of Formula I acted synergistically with Rituxan, as
calculated using the Chou-Talalay method.

[0413] In a DoHH2 xenograft model, it was observed that the compound of
Formula I inhibited tumor growth and that the combination of the compound
of Formula I with Rituxan significantly delayed time to tumor endpoint
(63%) at 30 mg/kg dose. Tumor growth inhibition was observed at 3 and 30
mpk of the compound of Formula I in combination with Rituxan (1 mg/kg),
at 45% and 55% on day 12, respectively. It was also observed that the
compound of Formula I significantly inhibited blood vessels counts in
tumor.

[0414] In a WSU-DLCL2 xenograft model, the combination of the compound of
Formula I with Rituxan (2 mg/kg iv qw) yielded 60% and 90% complete
regressions (tumor volume <25 mm3) at 3 and 30 mg, respectively.

[0417] It was observed that the compound of Formula I had a t1/2 of
230 min in human plasma. The oral pharmacokinetic parameters in mouse,
rat, and monkey are summarized in Tables 5 to 7. Exposures
(AUC.sub.(0-t)) of the compound of Formula I increased in a dose
proportional manner up to 30 mg/kg in SCID mouse, CD-IDS rat, and male
monkey. The compound of Formula I did not inhibit any megakaryocyte
progenitor cells at 10 μM.

[0418] The oral administration of the compound of Formula I at 100, 300,
and 10000 mg/kg/day for 7 consecutive days in the male CD-IGS rat
resulted generally in near dose proportional exposure increases. The
NOAEL was determined to be 1000 mg/kg/day.

6.4 In Vitro DLBCL Cell Thymidine Incorporation Assay

[0419] A panel of DLBCL cell lines of various cytogenetic features was
tested for their sensitivity to the antiproliferative activity of the
compound of Formula I (FIG. 2). Cells were treated with the compound of
Formula I for 5 days at 37° C.; proliferation of cells was
determined using 3H-thymidine incorporation method. Results of 3
independent experiments are shown (mean±SD) in FIG. 2. The compound
starting at 0.1-1 μM significantly (p<0.05) inhibited proliferation
of several lines of DLBCL cells, particularly ABC-subtype cells such as
Riva, U2932, TMD8, OCI-Ly3 and OCI-Ly10 cells. ABC-subtype cells appear
more sensitive to the antiproliferative effect than other subtype cells
including GCB-DLBCL and PMBL cells.

6.5 Inhibitory Effect on NFκB Activity in DLBCL Cells

[0420] DLBCL cells were treated with the compound of Formula I or an
IKK1/2 dual inhibitor (used as a positive inhibitor control) for 2 days.
NFκB activity was examined with Active Motif transcription factor
assay using nuclear extracts from cells following treatment. Results are
shown in FIG. 1 (mean±SD). The compound of Formula I significantly
inhibits NFκB p65 and p50 activity at concentrations of 0.1 μM,
1 μM and 10 μM. The compound of Formula I was found to inhibit the
NFκB activity in some DLBCL lines of the ABC subtype, such as U2932
and OCI-Ly10 cells. These results suggest that an effect on NFκB
signal transduction might be involved in the antiproliferative activity
of the compound of Formula I against ABC-DLBCL cells, and that the
baseline NFκB activity may be a predictive biomarker of lymphoma
tumor response to therapy with the compound.

6.6 In Vivo Mouse Xenograph Model for the OCI-LY10 Cell Subtype

[0421] Efficacy of the compound of Formula I against the OCI-Ly10 cell
subtype is investigated in an in vivo mouse xenograft model. Female CB.17
SCID mice age 6 to 12 weeks are injected with about 0.2 mL/mouse of
1×107 OCI-Ly10 tumor cells in 100% Matrigel sc in flank.
Treatment with the compound of Formula I begins once tumor reaches an
average size of 100 to 150 mg. Body weight is measured 5/2 and then
biweekly to the end of the study. Caliper measurement of the tumor is
performed biweekly. The endpoint of the study is tumor growth delay
(TGD). The percentage TGD is calculated. Animals are monitored
individually. The endpoint of the study is a tumor volume of about 1000
m3 or 60 days, whichever comes first. Responders to therapy may be
followed longer.

[0423] The ability of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione to
inhibit cancer cell growth was evaluated in a number of multiple myeloma
(MM) cell lines using in vitro and in vivo methods (FIGS. 5A & 5B).
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione was
shown to inhibit MM cell proliferation in a number of cell lines (FIGS.
5A, 5B & 6). For example, the antiproliferative effect of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione was
demonstrated in a N929 xenograft model (FIG. 6).

[0424] The effect of the protein cereblon (CRBN) on the efficacy of the
compound of Formula I to inhibit the proliferation, cell cycle
progression and/or cell invasion of various cancer cell lines was
studied. The compound of Formula I was found to interact with endogenous
myeloma CRBN and in a dose-dependent manner. The compound of Formula I
also interacts with HepG2 HCC CRBN in a dose-dependent manner. In
addition, the compound of Formula I was found to inhibit CRBN
ubiquitination with an IC50 of 208.7 μm.

[0425] ABC-DLBCL Cell Model

[0426] The expression of cereblon was found to modulate the efficacy of
the compound of Formula I against proliferation of ABC-DLBCL cell lines
(FIG. 7A-7C). Cereblon was required for inhibition of each of IRF4
expression, NFκB activity, and cell proliferation.

[0427] Myeloma Cell Models

[0428] The effect of cereblon in H929 myeloma cells was also evaluated.
H929 cells were transfected with mock, negative control siRNA and
CRBN-siRNA-7 for 24, 48, 72 and 96 hours. Cells were treated 24 h after
transfection with DMSO (0.1%) or the compound of Formula I for 1, 2, 3
days and the effect on cell cycle and proliferation investigated. The
compound of Formula I induced a delay of cell cycle progression, measured
as the decrease of the number of cells in S phase, in control mock and
negative control siRNA-transfected cells after 72 h treatment (FIG. 8).
Knockdown of CRBN markedly abrogated drug-induced delay in cell cycle
progression in H929 cells from 65 to 22% for the compound of Formula I.

[0429] RT-PCR and Western blot analysis was used to measure the levels of
key cell cycle and apoptotic regulators in order to further investigate
the effects of CRBN on the cell cycle arrest induced by the compound of
Formula I. In H929 cells, the cell cycle arrest in G1 phase by the
compound of Formula I coincides with a reduction of tumor suppressor,
pRb, phosphorylation and the oncogene and myeloma survival factor IRF4.
Western blot analysis showed that the compound of Formula I decreased
phosphorylation of pRB (FIGS. 9A & 9B) and total level of protein IRF4
(FIGS. 9C & 9D). The effect was reduced by knockdown of CRBN suggesting
that inhibition of cell cycle progression by the drugs requires CRBN
protein.

[0430] The compound of Formula I was found to inhibit the proliferation of
CRBN-sensitive MM cell lines U266, 100-1 and 1K-2 (FIG. 10).

[0431] Colorectal Cell Model

[0432] The expression of cereblon also modulates the anti-invasive
activity of the compound of Formula I in HCT-15 colorectal cancer cells
(FIG. 11). The ability of the compound of Formula Ito inhibit invasion of
HCT-15 cells was reduced by siCRBN.

6.9 Solid Tumor Models

[0433] The compound of Formula I was evaluated for its effect on solid
tumor cell lines from a variety of histologies (e.g., breast, ovarian,
colorectal, HCC). The compound of Formula I inhibits hypoxia-induced
HIF1-α expression in many such solid tumor cell lines (FIG.
12A-121). In addition, the compound of Formula I inhibits the invasion of
solid tumor cells to varying degrees (Table 10) and cell colony formation
(Table 11). The inhibition of solid tumor cell colony formation was
studied by a single high concentration treatment of the Compound of
formula I (10 μM) on day 1, followed by monitoring of cell colony
formation over the course of 10 to 20 days (Table 11, FIGS. 13A & 13B).

[0436] The compound of Formula I inhibited the production of (in order of
potency) TNF-α (IC50=0.034 μM), >IL-1β
(IC50=0.054 μM)>IL-6 (IC50=0.060 μM)>MDC
(IC50=0.062 μM)>MIP-1α (IC50=0.30 μM)>GM-CSF
(IC50=0.95 μM)>IL-8 (IC50>10 μM)>MIP-1β
(IC50>10 μM) (Table 12). The compound of Formula I also
enhanced IL-10, MCP-1, and RANTES production with mean percent of control
values of 480%, 236%, and 131%, respectively at the 0.1 μM
concentration.

[0437] The compound of formula I demonstrated potent inhibitory activity
in an in vitro assay of human umbilical vascular endothelial cell (HUVEC)
invasion. The compound of formula I strongly inhibited vascular
endothelial growth factor (VEGF)-, basic fibroblast growth factor
(bFGF)-, and hepatocyte growth factor (HGF)-induced invasion, weakly
inhibited VEGF and bFGF-induced HUVEC tube formation and migration, and
either enhanced or did not inhibit proliferation of growth factor-induced
HUVEC proliferation. The IC50 value for inhibition of VEGF-induced
HUVEC invasion was 0.29 nM. The IC50 value for inhibition of
bFGF-induced HUVEC invasion was 5.5 nM. The IC50 value for
inhibition of HGF-induced HUVEC invasion was 110 nM. The compound of
Formula I inhibited VEGF- and bFGF-induced migration 38% and 28%,
respectively at a concentration of 1 μM.

6.12 Clinical Protocol

[0438] A Phase 1a/1b, clinical study to determine the safety,
tolerability, pharmacokinetics and efficacy of the compound of Formula I
when administered orally to subjects with advanced solid tumors,
Non-Hodgkin's lymphoma, or multiple myeloma is provided. The
non-tolerated dose (NTD), the maximum tolerated dose (MTD) and the
recommended phase 2 dose (RP2D) are to be defined in the study. The
effect of the compound on biomarkers of angiogenesis in pre- and during
treatment tumor biopsies will be evaluated.

[0439] Study Design

[0440] The study is designed as a Phase 1a/1b study consisting of two
parts: dose escalation (Part A), and dose expansion (Part B). In Part A,
subjects will receive single and multiple ascending doses of the compound
of Formula I to measure pharmacokinetics (PK) and identify the maximum
tolerated dose (MTD) and the recommended phase 2 dose (RP2D). A standard
dose (3+3) escalation design (Simon et al., 1997) will be used to
identify initial toxicity. Initial cohorts of three subjects will be
given the compound of Formula I (0.5 mg once daily) in dose increments of
100% until the first instance of grade 3 or higher toxicity suspected to
be drug-related in the first cycle, at which point the particular cohort
will be expanded to a total of six subjects. This standard escalation
schedule will be initiated in order to establish the non-tolerated dose
(NTD) and MTD. Smaller increments and additional subjects within a dose
cohort may also be evaluated for safety. Approximately 20 to 40 subjects
will be treated and evaluated in Part A; however, the total number of
subjects in Part A depends on the number of dose cohorts needed to
establish the MTD. A dose will be considered the NTD when 2 or more out
of 6 evaluable subjects in a cohort experience drug-related dose limiting
toxicity (DLT) during Cycle 1. When the NTD is established, dose
escalation will stop. The MTD is defined as the last dose level below the
NTD with 0 or 1 out of 6 evaluable subjects experiencing DLT during Cycle
1. An intermediate dose (i.e., one between the NTD and the last dose
level before the NTD) or additional subjects within any dose cohort may
be required to more precisely determine the MTD and RP2D.

[0441] In Part B, subjects may start dosing at the MTD and/or a lower dose
level based on safety, PK and/or PD data from Part A. Approximately 100
subjects (up to 20 per cohort), stratified by tumor type, will be treated
and evaluated for safety and antitumor activity after every two cycles of
therapy. The dose, doses, or schedule appropriate will also be
determined. During Part B, safety data will be reviewed regularly
regarding the study continuation, as appropriate.

[0445] During the first cycle, only in Part A, each subject will be
administered a single daily dose of the compound of Formula I on Day 1
followed by a 48-hour observation and PK sampling period, followed on Day
1 by daily uninterrupted dosing for 28 days (Cycle 1=30 days). In
subsequent Part A cycles, subjects are treated in 28-day cycles with
continuous dosing from Day 1 to 28. The Compound of Formula I will be
given once or twice a day at a dose of 0.1, 0.5, 1, 2, 4, 5, 7.5, 10, 20,
25, or 50 mg in an initial dose. The dose may be of 0.1, 0.5, 1, 2, 4, 5,
7.5, 10 mg given once a day. The dose may be 50, 25, or 10 mg given twice
a day. The dose may be adjusted up, or down, from the starting dose
during treatment. As described above, if needed, the drug may be given in
a cyclical manner.

[0446] In Part B, subjects receive continuous dosing for 28 days from the
beginning--there is no post initial, single dose 48-hour PK collection
period.

[0447] Therapy will be discontinued if there is evidence of disease
progression, unacceptable toxicity or subject/physician decision to stop.
Subjects may continue to receive compound without interruption for as
long as they derive benefit as judged by the Investigator.

[0448] Enrollment is expected to occur over approximately 24 months.
Completion of active treatment and subject follow-up is expected to take
an additional 3-6 months

[0449] Study Treatments

[0450] Celgene Corporation will supply the compound of Formula I (HCl) as
0.1 mg, 0.5 mg, 1 mg and 3 mg capsules for oral administration. The
compound will be packaged in bottles inside boxes containing drug for 28
days.

[0451] In Part A (the dose escalation phase), the dose level will start at
0.5 mg once daily after the single PK dose. After the first dose is
administered to the last subject in any cohort, subjects are observed for
at least 30 days before the next higher, protocol-specified dose cohort
can begin. Intra subject dose escalation is not permitted unless approved
by the Safety Review Committee (SRC) which will consist of the principal
investigator and Celgene's medical monitor.

[0452] In Part B, subjects may receive the compound of Formula I at the
MTD and/or a lower dose level, based on safety, PK and PD evaluations
from Part A. Approximately 100 subjects (preselected tumor types in
groups of up to 20) will be evaluated for safety and antitumor effects.

[0453] Overview of Efficacy Assessments

[0454] Subjects will be evaluated for efficacy after every 2 cycles. The
primary efficacy variable is response. Tumor response will be based on
Response Evaluation Criteria in Solid Tumors (RECIST 1.1), International
Workshop Criteria (IWC) for NHL, International Uniform Response Criteria
for Multiple Myeloma (IURC) (Appendix A, Section 18.1), or Responses
Assessment for Neuro-Oncology (RANO) Working Group for GBM.

[0459] The PK profiles of the compound of Formula I and its metabolites
will be determined from serial blood and urine collections during the
first treatment cycle. These will be correlated with pharmacodynamic (PD)
outcomes where possible.

[0460] The examples set forth above are provided to give those of ordinary
skill in the art with a complete disclosure and description of how to
make and use the claimed embodiments, and are not intended to limit the
scope of what is disclosed herein. Modifications that are obvious to
persons of skill in the art are intended to be within the scope of the
following claims. All publications, patents, and patent applications
cited in this specification are incorporated herein by reference as if
each such publication, patent or patent application were specifically and
individually indicated to be incorporated herein by reference.